M. J. Berridge, M. D. Bootman, and R. H. , Calcium signalling: dynamics, homeostasis and remodeling, Nat Rev Mol Cell Biol, vol.4, pp.517-529, 2003.

M. J. Berridge, P. Lipp, and M. D. Bootman, The versatility and universality of calcium signaling, Nat Rev Mol Cell Biol, vol.1, pp.11-21, 2000.

T. Pozzan, R. Rizzuto, P. Volpe, and J. Meldolesi, Molecular and cellular physiology of intracellular calcium stores, Physiol Rev, vol.74, pp.595-636, 1994.

G. Csordás, P. Várnai, T. Golenár, S. Roy, G. Purkins et al., Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface, Mol. Cell, vol.39, pp.121-132, 2010.

M. Giacomello, I. Drago, M. Bortolozzi, M. Scorzeto, A. Gianelle et al., Ca 2 + hot spots on the mitochondrial surface are generated by Ca 2 + mobilization from stores, but not by activation of store-operated Ca 2 + channels, Mol. Cell, vol.38, pp.280-290, 2010.

D. E. Clapham, Calcium signaling, Cell, vol.131, pp.1047-1058, 2007.

T. A. Stewart, K. T. Yapa, and G. R. Monteith, Altered calcium signaling in cancer cells, Biochim. Biophys. Acta, vol.1848, pp.2502-2511, 2015.

D. Hanahan and R. A. Weinberg, The hallmarks of cancer, Cell, vol.100, pp.57-70, 2000.

N. Khadra, L. Bresson-bepoldin, B. Chaigne-delalande, A. Penna, M. D. Cahalan et al., Identification of a CD95-mediated negative feedback loop that hinders the DISC formation through an Orai1-Ca 2+ -PKC?2 signaling pathway, Proc Natl Acad Sci, vol.108, pp.19072-19077, 2011.

S. Tauzin, B. Chaigne-delalande, E. Selva, N. Khadra, S. Daburon et al., The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway, PLoS Biol, vol.9, p.1001090, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00681970

M. Malleter, S. Tauzin, A. Bessede, R. Castellano, A. Goubard et al., CD95L cell surface cleavage triggers a pro-metastatic signalling pathway in triple negative breast cancer, Cancer Res, vol.73, pp.6711-6721, 2013.

W. Schlegel, B. P. Winiger, P. Mollard, P. Vacher, F. Wuarin et al., Oscillations of cytosolic Ca 2+ in pituitary cells due to action potentials, Nature, vol.329, pp.719-721, 1987.

G. Grynkiewicz, M. Poenie, and R. Y. Tsien, A new generation of Ca 2+ indicators with greatly improved fluorescence properties, J Biol Chem, vol.260, pp.3440-3450, 1985.

L. Chen, X. Sha, X. Jiang, Y. Chen, Q. Ren et al., Pluronic/F127 mixed micelles for the delivery of Docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation, Int J Nanomedicine, vol.8, pp.73-84, 2013.

Y. Chen, X. Sha, W. Zhang, W. Zhong, Z. Fan et al., Pluronic mixed micelles overcoming methotrexate multidrug resistance : in vitro and in vivo evaluation, Int J Nanomedicine, vol.8, pp.1463-1476, 2013.

D. Y. Alakhova and A. V. Kabanov, Pluronics and MDR reversal: an update, Mol Pharm, vol.11, pp.2566-2578, 2014.

V. Y. Jo and C. Fletcher, WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition. Pathology (Phila), vol.46, pp.95-104, 2014.

K. M. Dalal, M. W. Kattan, C. R. Antonescu, M. F. Brennan, and S. Singer, Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk, Ann Surg, vol.244, issue.3, pp.381-91, 2006.

W. H. Henricks, Y. C. Chu, J. R. Goldblum, and S. W. Weiss, Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation, Am J Surg Pathol, vol.21, issue.3, pp.271-81, 1997.

S. H. Tirumani, H. Tirumani, J. P. Jagannathan, A. B. Shinagare, J. L. Hornick et al., Metastasis in dedifferentiated liposarcoma: Predictors and outcome in 148 patients, Eur J Surg Oncol EJSO, vol.41, issue.7, pp.899-904, 2015.

R. L. Jones, C. Fisher, O. Al-muderis, and J. Ir, 2853-60. 6. van der Graaf WTA. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, Eur J Cancer Oxf Engl, vol.41, issue.18, pp.1879-1886, 1990.

F. Lin, Z. Shen, X. Xu, B. Hu, S. Meerani et al., Evaluation of the Expression and Role of IGF Pathway Biomarkers in Human Sarcomas, Int J Immunopathol Pharmacol

J. Liang, B. Li, L. Yuan, and Z. Ye, Prognostic value of IGF-1R expression in bone and soft tissue sarcomas: a meta-analysis. OncoTargets Ther, vol.8, pp.1949-55, 2015.

A. Conti, V. Espina, A. Chiechi, G. Magagnoli, C. Novello et al., Mapping protein signal pathway interaction in sarcoma bone metastasis: linkage between rank, metalloproteinases turnover and growth factor signaling pathways, Clin Exp Metastasis, 2014.

Y. Tomita, T. Morooka, Y. Hoshida, B. Zhang, Y. Qiu et al., Prognostic Significance of Activated AKT Expression in Soft-Tissue Sarcoma, Clin Cancer Res, vol.12, issue.10, pp.3070-3077, 2006.

M. S. Benassi, L. Pazzaglia, C. Novello, I. Quattrini, S. Pollino et al., Tissue and serum IGFBP7 protein as biomarker in high-grade soft tissue sarcoma, Am J Cancer Res, vol.5, issue.11, pp.3446-54, 2015.

J. V. Tricoli, L. B. Rall, C. P. Karakousis, L. Herrera, N. J. Petrelli et al., Enhanced Levels of Insulin-like Growth Factor Messenger RNA in Human Colon Carcinomas and Liposarcomas, Cancer Res, vol.46, issue.12, pp.6169-73, 1986.

T. Peng, P. Zhang, J. Liu, T. Nguyen, S. Bolshakov et al., An experimental model for the study of well differentiated and dedifferentiated liposarcoma; deregulation of targetable tyrosine kinase receptors, Lab Investig J Tech Methods Pathol, vol.91, issue.3, pp.392-403, 2011.

J. Boucher, S. Softic, A. E. Ouaamari, M. T. Krumpoch, A. Kleinridders et al., Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function, Diabetes, vol.65, issue.8, pp.2201-2214, 2016.

A. Kasprzak, W. Kwasniewski, A. Adamek, and A. Gozdzicka-jozefiak, Insulin-like growth factor (IGF) axis in cancerogenesis, Mutat Res Mutat Res, vol.772, pp.78-104, 2017.

M. L. Miller, E. J. Molinelli, J. S. Nair, T. Sheikh, R. Samy et al., Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets, Sci Signal, vol.6, issue.294, p.85, 2013.

J. Janssen, A. J. Varewijck, A. S. Pappo, G. Vassal, J. J. Crowley et al., A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study. Cancer, vol.5, pp.2448-56, 2014.

. Kuro-o-m, Y. Matsumura, H. Aizawa, H. Kawaguchi, T. Suga et al., Mutation of the mouse klotho gene leads to a syndrome resembling ageing, Nature, vol.390, issue.6655, pp.45-51, 1997.

H. Kurosu, M. Yamamoto, J. D. Clark, J. V. Pastor, A. Nandi et al., Suppression of aging in mice by the hormone Klotho, Science, vol.309, issue.5742, pp.1829-1862, 2005.

C. Chen, T. Y. Tung, J. Liang, E. Zeldich, T. Zhou et al., Identification of cleavage sites leading to the shed form of the anti-aging protein klotho, Biochemistry (Mosc)

Y. Matsumura, H. Aizawa, T. Shiraki-iida, R. Nagai, M. Kuro-o et al., Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein, Biochem Biophys Res Commun, vol.242, issue.3, pp.626-656, 1998.

M. C. Hu, M. Kuro-o, and O. W. Moe, Renal and extrarenal actions of Klotho, Semin Nephrol, vol.33, issue.2, pp.118-147, 2013.

J. Fan and Z. Sun, The Antiaging Gene Klotho Regulates Proliferation and Differentiation of Adipose-Derived Stem Cells. Stem Cells Dayt Ohio, vol.34, pp.1615-1640, 2016.

V. Y. Jo and C. D. Fletcher, WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition, Pathology (Phila.), vol.46, pp.95-104, 2014.

M. A. Clark, C. Fisher, I. Judson, and J. M. Thomas, Soft-tissue sarcomas in adults, N. Engl J Med, vol.353, pp.701-711, 2005.

C. A. Stiller and D. M. Parkin, International variations in the incidence of childhood soft-tissue sarcomas, Paediatr Perinat Epidemiol, vol.8, pp.107-119, 1994.

C. Rubino, Radiation dose and risk of soft tissue and bone sarcoma after breast cancer treatment, Breast Cancer Res Treat, vol.89, pp.277-288, 2005.

Z. Burningham, M. Hashibe, L. Spector, and J. D. Schiffman, The Epidemiology of Sarcoma. Clin. Sarcoma Res, vol.2, p.14, 2012.

D. Coggon, G. Ntani, E. C. Harris, N. Jayakody, K. T. Palmer et al., WORKERS EXPOSED TO PHENOXY HERBICIDES: EXTENDED FOLLOW-UP OF A UK COHORT, vol.72, pp.435-441, 2015.

D. H. Kedes, The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission, Nat Med, vol.2, pp.918-924, 1996.

M. L. De-marchis, Desmoid Tumors in Familial Adenomatous Polyposis, Anticancer Res, vol.37, pp.3357-3366, 2017.

F. Ducimetière, Incidence of Sarcoma Histotypes and Molecular Subtypes in a Prospective Epidemiological Study with Central Pathology Review and Molecular Testing, PLoS ONE, vol.6, p.20294, 2011.

F. Chibon, Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity, Nat Med, vol.16, pp.781-787, 2010.

L. Lartigue, Genomic index predicts clinical outcome of intermediate-risk gastrointestinal stromal tumours, providing a new inclusion criterion for imatinib adjuvant therapy, Eur. J. Cancer Oxf. Engl, vol.51, pp.75-83, 1990.

F. Chibon, A subgroup of malignant fibrous histiocytomas is associated with genetic changes similar to those of well-differentiated liposarcomas, Cancer Genet Cytogenet, vol.139, pp.24-29, 2002.

C. Knebel, Prognostic factors and outcome of Liposarcoma patients: a retrospective evaluation over 15 years, BMC Cancer, vol.17, 2017.

J. J. Peterson, M. J. Kransdorf, L. W. Bancroft, and M. I. O'connor, Malignant fatty tumors: classification, clinical course, imaging appearance and treatment, Skeletal Radiol, vol.32, pp.493-503, 2003.

N. Mandahl, Scattered genomic amplification in dedifferentiated liposarcoma, Mol. Cytogenet, vol.10, 2017.

W. H. Henricks, Y. C. Chu, J. R. Goldblum, and S. W. Weiss, Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation, Am. J. Surg. Pathol, vol.21, pp.271-281, 1997.

S. H. Tirumani, Metastasis in dedifferentiated liposarcoma: Predictors and outcome in 148 patients, Eur. J. Surg. Oncol. EJSO, vol.41, pp.899-904, 2015.

F. Chibon and A. Aurias, Biologie moléculaire des sarcomes des tissus mous, pp.88-96, 2007.

A. A. Sandberg, Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma, Cancer Genet. Cytogenet, vol.155, pp.1-24, 2004.

C. R. Antonescu, Specificity of TLS-CHOP rearrangement for classic myxoid/round cell liposarcoma: absence in predominantly myxoid well-differentiated liposarcomas, J. Mol. Diagn. JMD, vol.2, pp.132-138, 2000.

J. Pérez-losada, Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma, Oncogene, vol.19, pp.6015-6022, 2000.

C. R. Antonescu, Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.7, pp.3977-3987, 2001.

F. Chibon, A subgroup of malignant fibrous histiocytomas is associated with genetic changes similar to those of well-differentiated liposarcomas, Cancer Genet. Cytogenet, vol.139, pp.24-29, 2002.

S. Gebhard, Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and followup analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group, Am J Surg Pathol, vol.26, pp.601-616, 2002.

K. M. Dalal, M. W. Kattan, C. R. Antonescu, M. F. Brennan, and S. Singer, Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk, Ann. Surg, vol.244, pp.381-391, 2006.

L. E. Matthyssens, D. Creytens, and W. P. Ceelen, Retroperitoneal Liposarcoma: Current Insights in Diagnosis and Treatment, Front. Surg, vol.2, 2015.

B. O'sullivan, Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial, Lancet Lond Engl, vol.359, pp.2235-2241, 2002.

A. Italiano, Advanced well-differentiated/dedifferentiated liposarcomas: role of chemotherapy and survival, Ann. Oncol. Off. J. Eur. Soc. Med. Oncol, vol.23, pp.1601-1607, 2012.

A. M. Crago and S. Singer, Clinical and Molecular Approaches to Well-differentiated and Dedifferentiated Liposarcoma, Curr. Opin. Oncol, vol.23, pp.373-378, 2011.

C. W. Ryan and J. Desai, The past, present, and future of cytotoxic chemotherapy and pathwaydirected targeted agents for soft tissue sarcoma, Am. Soc. Clin. Oncol. Educ. Book Am. Soc. Clin. Oncol. Meet, 2013.

A. Dufresne, Molecular biology of sarcoma and therapeutic choices

, Bull Cancer Paris, vol.102, pp.6-16, 2015.

P. G. Casali, Gastrointestinal stromal tumours: ESMO clinical recommendations for diagnosis, treatment and follow-up, Ann Oncol J Eur Soc Med Oncol, vol.20, pp.64-67, 2009.

J. F. Emile, Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs, Lancet Lond. Engl, vol.29, pp.1879-1886, 2012.
URL : https://hal.archives-ouvertes.fr/hal-00636301

C. Rodriguez-antona and M. Ingelman-sundberg, Cytochrome P450 pharmacogenetics and cancer, Oncogene, vol.25, pp.1679-1691, 2006.

S. N. Hochwald, D. M. Rose, M. F. Brennan, and M. E. Burt, Elevation of glutathione and related enzyme activities in high-grade and metastatic extremity soft tissue sarcoma, Ann. Surg. Oncol, vol.4, pp.303-309, 1997.

R. Zhuo, Targeting Glutathione S-transferase M4 in Ewing sarcoma, Front. Pediatr, vol.2, p.83, 2014.

J. Cummings, Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins, Biochem. Pharmacol, vol.67, pp.31-39, 2004.

H. Nakanishi, A. Myoui, T. Ochi, and K. Aozasa, P-glycoprotein expression in soft-tissue sarcomas, J. Cancer Res. Clin. Oncol, vol.123, pp.352-356, 1997.

Y. Oda, ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas, Int. J. Cancer, vol.114, pp.854-862, 2005.

A. Abolhoda, Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.5, pp.3352-3356, 1999.

R. Komdeur, Expression of multidrug resistance proteins, P-gp, MRP1 and LRP, in soft tissue sarcomas analysed according to their histological type and grade, Eur. J. Cancer Oxf. Engl, vol.39, pp.909-916, 1990.

K. Katayama, S. Yoshioka, S. Tsukahara, J. Mitsuhashi, and Y. Sugimoto, Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein, Mol. Cancer Ther, vol.6, pp.2092-2102, 2007.

M. Lima, Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair, Oncotarget, vol.7, pp.25885-25901, 2016.

S. Natarajan, S. Hombach-klonisch, P. Dröge, and T. Klonisch, HMGA2 inhibits apoptosis through interaction with ATR-CHK1 signaling complex in human cancer cells, vol.15, pp.263-280, 2013.

A. Italiano, HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon, Int. J. Cancer, vol.122, pp.2233-2241, 2008.
URL : https://hal.archives-ouvertes.fr/hal-00320104

M. Kappler, Elevated Expression Level of Survivin Protein in Soft-Tissue Sarcomas Is a Strong Independent Predictor of Survival, Clin. Cancer Res, vol.9, pp.1098-1104, 2003.

M. A. De-graaff, High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth, Transl. Oncol, vol.10, pp.546-554, 2017.

R. M. Gobble, Expression profiling of liposarcoma yields a multigene predictor of patient outcome and identifies genes that contribute to liposarcomagenesis, Cancer Res, vol.71, pp.2697-2705, 2011.

P. Juin, O. Geneste, F. Gautier, S. Depil, and M. Campone, Decoding and unlocking the BCL-2 dependency of cancer cells, Nat. Rev. Cancer, vol.13, pp.455-465, 2013.

J. T. Erler, Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance, Mol. Cell. Biol, vol.24, pp.2875-2889, 2004.

T. Köhler, High bad and bcl-xL gene expression and combined bad, bcl-xL, bax and bcl-2 mRNA levels: molecular predictors for survival of stage 2 soft tissue sarcoma patients, Anticancer Res, vol.22, pp.1553-1559, 2002.

V. Kirkin, S. Joos, and M. Zörnig, The role of Bcl-2 family members in tumorigenesis, Biochim. Biophys. Acta BBA -Mol. Cell Res, vol.1644, pp.229-249, 2004.

M. A. De-graaff, Inhibition of Bcl-2 family members sensitises soft tissue leiomyosarcomas to chemotherapy, Br. J. Cancer, vol.114, pp.1219-1226, 2016.

E. W. Lapensee, S. P. Reddy, E. R. Hugo, S. J. Schwemberger, and N. Ben-jonathan, LS14 cells: a model for chemoresistance in liposarcoma, Cancer Biol. Ther, vol.6, pp.519-524, 2007.

A. R. Delbridge, S. Grabow, A. Strasser, and D. L. Vaux, Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies, Nat. Rev. Cancer, vol.16, pp.99-109, 2016.

D. Reynoso, Synergistic induction of apoptosis by the Bcl-2 inhibitor ABT-737 and imatinib mesylate in gastrointestinal stromal tumor cells, Mol. Oncol, vol.5, pp.93-104, 2011.

A. M. Vincent and E. L. Feldman, Control of cell survival by IGF signaling pathways, Growth Horm. IGF Res. Off. J. Growth Horm. Res. Soc. Int. IGF Res. Soc, vol.12, pp.193-197, 2002.

F. Lin, Evaluation of the Expression and Role of IGF Pathway Biomarkers in Human Sarcomas, Int. J. Immunopathol. Pharmacol, vol.26, pp.169-177, 2013.

J. Liang, B. Li, L. Yuan, and Z. Ye, Prognostic value of IGF-1R expression in bone and soft tissue sarcomas: a meta-analysis, OncoTargets Ther, vol.8, pp.1949-1955, 2015.

A. Conti, Mapping protein signal pathway interaction in sarcoma bone metastasis: linkage between rank, metalloproteinases turnover and growth factor signaling pathways, Clin. Exp. Metastasis, vol.31, pp.15-24, 2014.

Y. Tomita, Prognostic Significance of Activated AKT Expression in Soft-Tissue Sarcoma, Clin. Cancer Res, vol.12, pp.3070-3077, 2006.

J. V. Tricoli, Enhanced Levels of Insulin-like Growth Factor Messenger RNA in Human Colon Carcinomas and Liposarcomas, Cancer Res, vol.46, p.242, 1986.

T. Peng, An experimental model for the study of well differentiated and dedifferentiated liposarcoma; deregulation of targetable tyrosine kinase receptors, Lab. Investig. J. Tech. Methods Pathol, vol.91, pp.392-403, 2011.

D. Kanojia, Genomic landscape of liposarcoma, Oncotarget, vol.6, pp.42429-42444, 2015.

M. S. Benassi, Tissue and serum IGFBP7 protein as biomarker in high-grade soft tissue sarcoma, Am. J. Cancer Res, vol.5, pp.3446-3454, 2015.

H. King, T. Aleksic, P. Haluska, and V. M. Macaulay, Can we unlock the potential of IGF-1R inhibition in cancer therapy?, Cancer Treat. Rev, vol.40, pp.1096-1105, 2014.

M. Wachtel, FGFR4 signaling couples to Bim and not Bmf to discriminate subsets of alveolar rhabdomyosarcoma cells, Int. J. Cancer, vol.135, pp.1543-1552, 2014.

X. Zeng, H. Zhang, A. Oh, Y. Zhang, and D. Yee, Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor, Breast Cancer Res. Treat, vol.133, pp.117-126, 2012.

X. Zeng, D. Sachdev, H. Zhang, M. Gaillard-kelly, and D. Yee, Sequencing of type I insulin-like growth factor receptor inhibition affects chemotherapy response in vitro and in vivo, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.15, pp.2840-2849, 2009.

M. L. Miller, Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets, Sci. Signal, vol.6, p.85, 2013.

L. T. Vassilev, Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics, Cell Cycle Georget. Tex, vol.3, pp.419-421, 2004.

D. G. Morris, A Phase II Study of Flavopiridol in Patients With Previously Untreated Advanced Soft Tissue Sarcoma, Sarcoma, p.64374, 2006.

J. Kao, Phase 1 study of concurrent sunitinib and image-guided radiotherapy followed by maintenance sunitinib for patients with oligometastases: acute toxicity and preliminary response, Cancer, vol.115, pp.3571-3580, 2009.

R. Porzio, M. A. Bella, G. Rossi, and A. Ardizzoni, Long-lasting clinical benefit of sunitinib malate in the treatment of a case of heavily pre-treated metastatic liposarcoma, Anticancer Res, vol.33, pp.1061-1063, 2013.

G. Ranieri, Pazopanib a tyrosine kinase inhibitor with strong anti-angiogenetic activity: a new treatment for metastatic soft tissue sarcoma, Crit. Rev. Oncol. Hematol, vol.89, pp.322-329, 2014.

S. P. Chawla, Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.30, pp.78-84, 2012.
URL : https://hal.archives-ouvertes.fr/hal-01058262

A. Belfiore, M. Genua, and R. Malaguarnera, PPAR-? Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer, PPAR Res, 2009.

M. Kuro-o, Mutation of the mouse klotho gene leads to a syndrome resembling ageing, Nature, vol.390, pp.45-51, 1997.

J. R. Aunan, W. C. Cho, and K. Søreide, The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks, Aging Dis, vol.8, pp.628-642, 2017.

S. O. Iseghohi and K. Omage, How ageing increases cancer susceptibility: A tale of two opposing yet synergistic views, Genes Dis, vol.3, pp.105-109, 2016.

G. Pawelec and R. Solana, Are cancer and ageing different sides of the same coin? Conference on Cancer and Ageing, EMBO Rep, vol.9, pp.234-238, 2008.

T. Finkel, M. Serrano, and M. A. Blasco, The common biology of cancer and ageing, Nature, vol.448, 2007.

J. Campisi, Aging, Cellular Senescence, and Cancer, Annu. Rev. Physiol, vol.75, pp.685-705, 2013.

C. Falandry, M. Bonnefoy, G. Freyer, and E. Gilson, Biology of Cancer and Aging: A Complex Association With Cellular Senescence, J. Clin. Oncol, vol.32, pp.2604-2610, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01859025

Y. Matsumura, Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein, Biochem. Biophys. Res. Commun, vol.242, pp.626-630, 1998.

C. Chen, S. Podvin, E. Gillespie, S. E. Leeman, and C. R. Abraham, Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17, Proc. Natl. Acad. Sci. U. S. A, vol.104, pp.19796-19801, 2007.

L. Bloch, Klotho is a substrate for alpha-, beta-and gamma-secretase, FEBS Lett, vol.583, pp.3221-3224, 2009.

C. Chen, Identification of cleavage sites leading to the shed form of the anti-aging protein klotho, Biochemistry (Mosc.), vol.53, pp.5579-5587, 2014.

T. Shiraki-iida, Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein, FEBS Lett, vol.424, pp.6-10, 1998.

A. Imura, alpha-Klotho as a regulator of calcium homeostasis, Science, vol.316, pp.1615-1618, 2007.

D. C. German, I. Khobahy, J. Pastor, M. Kuro-o, and X. Liu, Nuclear localization of Klotho in brain: an anti-aging protein, Neurobiol. Aging, vol.33, pp.25-30, 1483.

M. Suzuki, ?Klotho Is Required for Fibroblast Growth Factor (FGF) 21 Signaling through FGF Receptor (FGFR) 1c and FGFR3c, Mol. Endocrinol, vol.22, pp.1006-1014, 2008.

X. Wu, Co-receptor requirements for fibroblast growth factor-19 signaling, J. Biol. Chem, vol.282, pp.29069-29072, 2007.

Y. Yamazaki, Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects, Biochem. Biophys. Res. Commun, vol.398, pp.513-518, 2010.

Q. Zhou, Role of Fosinopril and Valsartan on Klotho Gene Expression Induced by

, Angiotensin II in Rat Renal Tubular Epithelial Cells, Kidney Blood Press. Res, vol.33, pp.186-192, 2010.

Z. Xu, H. Gao, K. Ou-yang, S. Cai, and Y. Hu, Establishment of a cell-based assay to screen regulators for Klotho gene promoter, Acta Pharmacol. Sin, vol.25, p.244, 2004.

B. H. Choi, C. G. Kim, Y. Lim, Y. H. Lee, and S. Y. Shin, Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1, Gene, vol.450, pp.121-127, 2010.

D. Jung, Y. Xu, and Z. Sun, Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands, Oncotarget, vol.8, pp.46745-46755, 2017.

W. L. Lau, Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet, Kidney Int, vol.82, pp.1261-1270, 2012.

R. R. Alcendor, Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart, Circ. Res, vol.100, pp.1512-1521, 2007.

R. Watanabe, Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions, Sci. Rep, vol.7, 2017.

H. Sugiura, Recombinant human erythropoietin mitigates reductions in renal klotho expression, Am. J. Nephrol, vol.32, pp.137-144, 2010.

L. Chen, M. Cheng, P. Ku, and J. Lin, Rosiglitazone Increases Cerebral Klotho Expression to Reverse Baroreflex in Type 1-Like Diabetic Rats, BioMed Res. Int, 2014.

K. G. Avin, Skeletal muscle as a regulator of the longevity protein, Klotho. Front. Physiol, vol.5, 2014.

E. Mostafidi, A. Moeen, H. Nasri, and G. Hagjo, A. & Ardalan, M. Serum Klotho Levels in Trained Athletes. Nephro-Urol. Mon, vol.8, 2016.

X. Han, Role of estrogen receptor ? and ? in preserving hippocampal function during aging, J. Neurosci. Off. J. Soc. Neurosci, vol.33, pp.2671-2683, 2013.

S. Hsu, Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway, Biochem. J, vol.464, pp.221-229, 2014.

S. Hsu, Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway, Int. J. Biochem. Cell Biol, vol.53, pp.361-371, 2014.

R. Marsell, Gene expression analysis of kidneys from transgenic mice expressing fibroblast growth factor-23, Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. -Eur. Ren. Assoc, vol.23, pp.827-833, 2008.

H. E. Yoon, Angiotensin II blockade upregulates the expression of Klotho, the antiageing gene, in an experimental model of chronic cyclosporine nephropathy, Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. -Eur. Ren. Assoc, vol.26, pp.800-813, 2011.

L. Zhou, Y. Li, D. Zhou, R. J. Tan, and Y. Liu, Loss of Klotho Contributes to Kidney Injury by Derepression of Wnt/?-Catenin Signaling, J. Am. Soc. Nephrol. JASN, vol.24, pp.771-785, 2013.

J. A. Moreno, The inflammatory cytokines TWEAK and TNF? reduce renal klotho expression through NF?B, J. Am. Soc. Nephrol. JASN, vol.22, pp.1315-1325, 2011.

W. Kang and G. Xu, Atrasentan increased the expression of klotho by mediating miR-199b-5p and prevented renal tubular injury in diabetic nephropathy, Sci. Rep, vol.6, p.245, 2016.

H. Olauson, R. Mencke, J. Hillebrands, and T. E. Larsson, Tissue expression and source of circulating ?Klotho, Bone, vol.100, pp.19-35, 2017.

K. Lim, ?-Klotho Expression in Human Tissues, J. Clin. Endocrinol. Metab, vol.100, pp.1308-1318, 2015.

S. Ichikawa, A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis, J. Clin. Invest, vol.117, pp.2684-2691, 2007.

C. A. Brownstein, A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism, Proc. Natl. Acad. Sci. U. S. A, vol.105, pp.3455-3460, 2008.

C. Liu, Klotho gene polymorphisms are related to colorectal cancer susceptibility, Int. J. Clin. Exp. Pathol, vol.8, pp.7446-7449, 2015.

S. Jo, KLOTHO gene polymorphism is associated with coronary artery stenosis but not with coronary calcification in a Korean population, Int. Heart. J, vol.50, pp.23-32, 2009.

D. Telci, KLOTHO gene polymorphism of G395A is associated with kidney stones, Am. J. Nephrol, vol.33, pp.337-343, 2011.

K. Kawano, Klotho gene polymorphisms associated with bone density of aged postmenopausal women, J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res, vol.17, pp.1744-1751, 2002.

D. J. Friedman, Klotho variants and chronic hemodialysis mortality, J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res, vol.24, pp.1847-1855, 2009.

C. Baldwin, Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis, Blood, vol.106, pp.372-375, 2005.

N. Ogata, Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women, Bone, vol.31, pp.37-42, 2002.

V. Majumdar and R. Christopher, Association of exonic variants of Klotho with metabolic syndrome in Asian Indians, Clin. Chim. Acta Int. J. Clin. Chem, vol.412, pp.1116-1121, 2011.

E. Rhee, The differential effects of age on the association of KLOTHO gene polymorphisms with coronary artery disease, Metabolism, vol.55, pp.1344-1351, 2006.

C. Xu, Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in Eastern China, Gene, vol.526, pp.494-497, 2013.

D. E. Arking, Association of human aging with a functional variant of klotho, Proc. Natl. Acad. Sci. U. S. A, vol.99, pp.856-861, 2002.

T. Zhou, T. B. King, G. D. Chen, C. Abraham, and C. R. , Biochemical and functional characterization of the klotho-VS polymorphism implicated in aging and disease risk, J. Biol. Chem, vol.288, pp.36302-36311, 2013.

D. B. Dubal, Life extension factor klotho enhances cognition, Cell Rep, vol.7, pp.1065-1076, 2014.

O. P. Almeida, Longevity Klotho gene polymorphism and the risk of dementia in older men, Maturitas, vol.101, pp.1-5, 2017.

I. Wolf, Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin, Oncogene, vol.29, pp.26-33, 2010.

Y. Laitman, The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers, Breast Cancer Res. Treat, vol.132, pp.1119-1126, 2012.

L. Wang, Klotho is silenced through promoter hypermethylation in gastric cancer, Am. J. Cancer Res, vol.1, pp.111-119, 2011.

B. Xie, Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer, Cancer Cell Int, vol.13, p.18, 2013.

L. Abramovitz, KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.17, pp.4254-4266, 2011.

B. Xie, Hmgb1 inhibits Klotho expression and malignant phenotype in melanoma cells by activating NF-?B, Oncotarget, vol.7, pp.80765-80782, 2016.

J. Pan, Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer, Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med, vol.32, pp.729-735, 2011.

T. Rubinek, Epigenetic silencing of the tumor suppressor klotho in human breast cancer, Breast Cancer Res. Treat, vol.133, pp.649-657, 2012.

L. Gan, J. Pan, S. Chen, J. Zhong, and L. Wang, DNA methylation of ZIC1 and KLOTHO gene promoters in colorectal carcinomas and its clinicopathological significance

, Med. Sci, vol.40, pp.309-314, 2011.

J. Lee, The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma, Mol. Cancer, vol.9, p.109, 2010.

B. Jiang, Y. Gu, and Y. Chen, Identification of novel predictive markers for the prognosis of pancreatic ductal adenocarcinoma, Cancer Invest, vol.32, pp.218-225, 2014.

B. Xie, Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma, Hum. Pathol, vol.44, pp.795-801, 2013.

X. He, Up-regulated miR-199a-5p in gastric cancer functions as an oncogene and targets klotho, BMC Cancer, vol.14, p.218, 2014.

S. J. Mehi, A. Maltare, C. R. Abraham, and G. D. King, MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro, Age, vol.36, pp.141-149, 2014.

K. Morishita, The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc, J. Nutr, vol.131, pp.3182-3188, 2001.

T. Shimada, Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism, J. Clin. Invest, vol.113, pp.561-568, 2004.

M. Hesse, L. F. Fröhlich, U. Zeitz, B. Lanske, and R. G. Erben, Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice, Matrix Biol. J. Int. Soc. Matrix Biol, vol.26, pp.75-84, 2007.

M. Ohnishi, T. Nakatani, B. Lanske, and M. S. Razzaque, Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase, Kidney Int, vol.75, pp.1166-1172, 2009.

T. Nakatani, In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis, FASEB J, vol.23, pp.433-441, 2009.

K. Fon-tacer, Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse, Mol. Endocrinol. Baltim. Md, vol.24, pp.2050-2064, 2010.

H. Segawa, Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice, Am. J. Physiol. -Ren. Physiol, vol.292, pp.769-779, 2007.

M. C. Hu, Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule, FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol, vol.24, pp.3438-3450, 2010.

O. Tohyama, Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid betaglucuronides, J. Biol. Chem, vol.279, pp.9777-9784, 2004.

C. Huang, Regulation of ion channels by secreted Klotho, Adv. Exp. Med. Biol, vol.728, pp.100-106, 2012.

T. E. Woudenberg-vrenken, Characterization of vitamin D-deficient klotho(-/-) mice: do increased levels of serum 1,25(OH)2D3 cause disturbed calcium and phosphate homeostasis in klotho(-/-) mice?, Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. -Eur. Ren. Assoc, vol.27, pp.4061-4068, 2012.

R. T. Alexander, Klotho prevents renal calcium loss, J. Am. Soc. Nephrol. JASN, vol.20, pp.2371-2379, 2009.

R. G. Erben and O. Andrukhova, FGF23-Klotho signaling axis in the kidney, Bone, vol.100, pp.62-68, 2017.

Q. Chang, The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel, Science, vol.310, pp.490-493, 2005.

P. Lu, S. Boros, Q. Chang, R. J. Bindels, and J. G. Hoenderop, The beta-glucuronidase klotho exclusively activates the epithelial Ca2+ channels TRPV5 and TRPV6, Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. -Eur. Ren. Assoc, vol.23, pp.3397-3402, 2008.

M. T. Wolf, S. An, M. Nie, M. S. Bal, and C. Huang, Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra-and extracellular N-glycosylationdependent mechanisms, J. Biol. Chem, vol.289, pp.35849-35857, 2014.

S. Cha, Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho, Mol. Pharmacol, vol.76, pp.38-46, 2009.

P. A. Welling and K. Ho, A comprehensive guide to the ROMK potassium channel: form and function in health and disease, Am. J. Physiol. -Ren. Physiol, vol.297, pp.849-863, 2009.

Y. Lin and Z. Sun, Antiaging gene Klotho enhances glucose-induced insulin secretion by upregulating plasma membrane levels of TRPV2 in MIN6 ?-cells, Endocrinology, vol.153, pp.3029-3039, 2012.

T. Kusaba, Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity, Proc. Natl. Acad. Sci. U. S. A, vol.107, pp.19308-19313, 2010.

Y. Wu, Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho, Kidney Int, vol.91, pp.830-841, 2017.

G. Dalton, Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling, Proc. Natl. Acad. Sci. U. S. A, vol.114, pp.752-757, 2017.

J. D. Wright, Modeled structural basis for the recognition of ?2-3-sialyllactose by soluble Klotho, FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol, vol.31, pp.3574-3586, 2017.

T. Utsugi, Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging, Metabolism, vol.49, pp.1118-1123, 2000.

H. Kurosu, Suppression of aging in mice by the hormone Klotho, Science, vol.309, pp.1829-1833, 2005.

B. Xie, J. Chen, B. Liu, and J. Zhan, Klotho Acts as a Tumor Suppressor in Cancers, Pathol. Oncol. Res, vol.19, pp.611-617, 2013.

L. Girnita, Inhibition of N-linked glycosylation down-regulates insulin-like growth factor-1 receptor at the cell surface and kills Ewing's sarcoma cells: therapeutic implications, Anticancer. Drug Des, vol.15, pp.67-72, 2000.

A. Sasaki, Overexpression of plasma membrane-associated sialidase attenuates insulin signaling in transgenic mice, J. Biol. Chem, vol.278, pp.27896-27902, 2003.

J. Xie, Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart, Nat. Commun, vol.3, p.1238, 2012.

I. Seim, Genome analysis reveals insights into physiology and longevity of the Brandt's bat Myotis brandtii, Nat. Commun, vol.4, 2013.

S. Ma and V. N. Gladyshev, Molecular signatures of longevity: Insights from cross-species comparative studies, Semin. Cell Dev. Biol

J. B. Dorman, B. Albinder, T. Shroyer, and C. Kenyon, The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans, Genetics, vol.141, pp.1399-1406, 1995.

D. J. Clancy, Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein, Science, vol.292, pp.104-106, 2001.

M. Barbieri, M. Bonafè, C. Franceschi, and G. Paolisso, Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans, Am. J. Physiol. Endocrinol. Metab, vol.285, pp.1064-1071, 2003.

H. M. Brown-borg, Longevity in mice: is stress resistance a common factor?, Age Dordr. Neth, vol.28, pp.145-162, 2006.

T. Chiba, H. Yamaza, and I. Shimokawa, Role of Insulin and Growth Hormone/Insulin-Like Growth Factor-I Signaling in Lifespan Extension: Rodent Longevity Models for Studying Aging and Calorie Restriction, Curr. Genomics, vol.8, pp.423-428, 2007.

S. Murakami, Stress resistance in long-lived mouse models, Exp. Gerontol, vol.41, pp.1014-1019, 2006.

X. Sun, W. Chen, and Y. Wang, DAF-16/FOXO Transcription Factor in Aging and Longevity, Front. Pharmacol, vol.8, p.548, 2017.

D. H. Kim, The roles of FoxOs in modulation of aging by calorie restriction, Biogerontology, vol.16, pp.1-14, 2015.

E. M. Mercken, Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile, Aging Cell, vol.12, pp.645-651, 2013.

M. A. Madsen, Altered oxidative stress response of the long-lived Snell dwarf mouse, Biochem. Biophys. Res. Commun, vol.318, pp.998-1005, 2004.

Y. Son, Mitogen-Activated Protein Kinases and Reactive Oxygen Species: How Can ROS Activate MAPK Pathways?, J. Signal Transduct, 2011.

K. T. Pfaffenbach, GRP78/BiP is a novel downstream target of IGF-1 receptor mediated signaling, J. Cell. Physiol, vol.227, pp.3803-3811, 2012.

R. Novosyadlyy, Insulin-like growth factor-I protects cells from ER stress-induced apoptosis via enhancement of the adaptive capacity of endoplasmic reticulum, Cell Death Differ, vol.15, pp.1304-1317, 2008.

A. A. Sadighi-akha, Heightened Induction of Proapoptotic Signals in Response to Endoplasmic Reticulum Stress in Primary Fibroblasts from a Mouse Model of Longevity, J. Biol. Chem, vol.286, pp.30344-30351, 2011.

S. Henis-korenblit, Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity, Proc. Natl. Acad. Sci. U. S. A, vol.107, pp.9730-9735, 2010.

S. Banerjee, Klotho ameliorates chemically induced endoplasmic reticulum (ER) stress signaling, Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol, vol.31, pp.659-672, 2013.

S. Song, P. Gao, H. Xiao, Y. Xu, and L. Y. Si, Klotho Suppresses Cardiomyocyte Apoptosis in Mice with Stress-Induced Cardiac Injury via Downregulation of Endoplasmic Reticulum Stress, PLoS ONE, vol.8, 2013.

Q. Liu, Ameliorating effect of Klotho on endoplasmic reticulum stress and renal fibrosis induced by unilateral ureteral obstruction, Iran. J. Kidney Dis, vol.9, pp.291-297, 2015.

Z. Laron, R. Kauli, L. Lapkina, and H. Werner, IGF-I deficiency, longevity and cancer protection of patients with Laron syndrome, Mutat. Res. Rev. Mutat. Res, vol.772, pp.123-133, 2017.

K. Flurkey, J. Papaconstantinou, R. A. Miller, and D. E. Harrison, Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production, Proc. Natl. Acad. Sci. U. S. A, vol.98, pp.6736-6741, 2001.

F. Bielschowsky and M. Bielschowsky, Carcinogenesis in the Pituitary Dwarf Mouse. The Response to Dimethylbenzanthracene Applied to the Skin, Br. J. Cancer, vol.15, pp.257-262, 1961.

E. G. Rennels, D. M. Anigstein, and L. Anigstein, A cumulative study of the growth of sarcoma 180 in anterior pituitary dwarf mice, Tex. Rep. Biol. Med, vol.23, pp.776-781, 1965.

H. Liu, Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging, Science, vol.317, pp.803-806, 2007.

L. Yu, W. Meng, J. Ding, and M. Cheng, Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT1R/beta catenin pathway, Biochem. Biophys. Res. Commun, vol.473, pp.455-461, 2016.

E. M. De-cavanagh, F. Inserra, and L. Ferder, Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria?, Cardiovasc. Res, vol.89, pp.31-40, 2011.

E. M. De-cavanagh, F. Inserra, and L. Ferder, Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition, Am. J. Physiol. Heart Circ. Physiol, vol.309, pp.15-44, 2015.

I. Mizuno, Y. Takahashi, Y. Okimura, H. Kaji, and K. Chihara, Upregulation of the klotho gene expression by thyroid hormone and during adipose differentiation in 3T3-L1 adipocytes, Life Sci, vol.68, pp.2917-2923, 2001.

Y. Chihara, Klotho protein promotes adipocyte differentiation, Endocrinology, vol.147, pp.3835-3842, 2006.

J. Fan and Z. Sun, The Antiaging Gene Klotho Regulates Proliferation and Differentiation of Adipose-Derived Stem Cells, Stem Cells Dayt. Ohio, vol.34, pp.1615-1625, 2016.

Y. Yang, Neonatal Maternal Separation Impairs Prefrontal Cortical Myelination and Cognitive Functions in Rats Through Activation of Wnt Signaling, Cereb. Cortex N. Y. N, pp.2871-2884, 2017.

C. Chen, The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS, J. Neurosci. Off. J. Soc. Neurosci, vol.33, pp.1927-1939, 2013.

C. R. Abraham, P. C. Mullen, T. Tucker-zhou, C. D. Chen, E. Zeldich et al., Is a Neuroprotective and Cognition-Enhancing Protein. in Vitamins & Hormones, vol.101, pp.215-238, 2016.

S. Fujimaki, T. Wakabayashi, T. Takemasa, M. Asashima, and T. Kuwabara, The regulation of stem cell aging by Wnt signaling, Histol. Histopathol, vol.30, pp.1411-1430, 2015.

M. Wehling-henricks, Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy, Hum. Mol. Genet, vol.25, pp.2465-2482, 2016.

X. Tang, Klotho: a tumor suppressor and modulator of the Wnt/?-catenin pathway in human hepatocellular carcinoma, Lab. Investig. J. Tech. Methods Pathol, vol.96, pp.197-205, 2016.

R. Nusse and H. Clevers, Wnt/?-Catenin Signaling, Disease, and Emerging Therapeutic Modalities, Cell, vol.169, pp.985-999, 2017.

S. Doi, Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice, J. Biol. Chem, vol.286, pp.8655-8665, 2011.

Q. Liu, Klotho mitigates cyclosporine A (CsA)-induced epithelial-mesenchymal transition (EMT) and renal fibrosis in rats, Int. Urol. Nephrol, vol.49, pp.345-352, 2017.

Y. Maekawa, Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation, Endocrine, vol.35, pp.341-346, 2009.

X. Guan, Klotho suppresses renal tubulo-interstitial fibrosis by controlling basic fibroblast growth factor-2 signalling, J. Pathol, vol.234, pp.560-572, 2014.

J. Donate-correa, Klotho in cardiovascular disease: Current and future perspectives, World J. Biol. Chem, vol.6, pp.351-357, 2015.

G. Corsetti, Decreased expression of Klotho in cardiac atria biopsy samples from patients at higher risk of atherosclerotic cardiovascular disease, J. Geriatr. Cardiol. JGC, vol.13, pp.701-711, 2016.

Y. Saito, Klotho protein protects against endothelial dysfunction, Biochem. Biophys. Res. Commun, vol.248, pp.324-329, 1998.

T. Shimada, Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse, Circulation, vol.110, pp.1148-1155, 2004.

Y. Saito, In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome, Biochem. Biophys. Res. Commun, vol.276, pp.767-772, 2000.

T. Nagai, Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress, FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol, vol.17, pp.50-52, 2003.

M. Yamamoto, Regulation of oxidative stress by the anti-aging hormone klotho, J. Biol. Chem, vol.280, pp.38029-38034, 2005.

M. Hu, The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection, Kidney Int, vol.84, pp.468-481, 2013.

H. Rakugi, Anti-oxidative effect of Klotho on endothelial cells through cAMP activation, Endocrine, vol.31, pp.82-87, 2007.

G. Maltese, The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells, J. Cell. Mol. Med, vol.21, pp.621-627, 2017.

A. M. Laszczyk, Klotho regulates postnatal neurogenesis and protects against agerelated spatial memory loss, Neurobiol. Aging, vol.59, pp.41-54, 2017.

D. B. Dubal, Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice, J. Neurosci. Off. J. Soc. Neurosci, vol.35, pp.2358-2371, 2015.

J. Leon, Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and ?-Synuclein Transgenic Mice, Cell Rep, vol.20, pp.1360-1371, 2017.

S. Inoue, Sepsis-induced hypercytokinemia and lymphocyte apoptosis in agingaccelerated Klotho knockout mice, Shock Augusta Ga, vol.39, pp.311-316, 2013.

S. Okada, Impairment of B lymphopoiesis in precocious aging (klotho) mice, Int. Immunol, vol.12, pp.861-871, 2000.

R. D. Thurston, Downregulation of aging-related Klotho gene in experimental colitis: the role of TNF and IFN-?, Gastroenterology, vol.138, 2010.

Y. Zhao, Klotho Depletion Contributes to Increased Inflammation in Kidney of the db/db Mouse Model of Diabetes via RelA (Serine)536 Phosphorylation, Diabetes, vol.60, pp.1907-1916, 2011.

F. Liu, S. Wu, H. Ren, and J. Gu, Klotho suppresses RIG-I-mediated senescence-associated inflammation, Nat. Cell Biol, vol.13, pp.254-262, 2011.

M. Ikushima, Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells, Biochem. Biophys. Res. Commun, vol.339, pp.827-832, 2006.

J. Carracedo, Klotho modulates the stress response in human senescent endothelial cells, Mech. Ageing Dev, vol.133, pp.647-654, 2012.

Y. Maekawa, Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway, Geriatr. Gerontol. Int, vol.11, pp.510-516, 2011.

G. M. Wahl and A. M. Carr, The evolution of diverse biological responses to DNA damage: insights from yeast and p53, Nat. Cell Biol, vol.3, pp.277-286, 2001.

R. M. De-oliveira, Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway, FEBS Lett, vol.580, pp.5753-5758, 2006.

P. Buendía, Klotho Prevents NF?B Translocation and Protects Endothelial Cell From Senescence Induced by Uremia, J. Gerontol. A. Biol. Sci. Med. Sci, vol.70, pp.1198-1209, 2015.

Y. Zhu, Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3?/Snail signaling in renal cell carcinoma, Cancer Sci, vol.104, pp.663-671, 2013.

X. Li, Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway, Int. J. Oncol, vol.45, pp.611-618, 2014.

I. Wolf, Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer, Oncogene, vol.27, pp.7094-7105, 2008.

I. Lojkin, Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer, Cancer Lett, vol.362, pp.149-157, 2015.

X. Tang, Expression of klotho and ?-catenin in esophageal squamous cell carcinoma, and their clinicopathological and prognostic significance, Dis. Esophagus Off. J. Int. Soc. Dis. Esophagus, vol.29, pp.207-214, 2016.

C. Chen, The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line, J. Mol. Neurosci. MN, vol.55, pp.76-90, 2015.

S. Feng, O. Dakhova, C. J. Creighton, and M. Ittmann, Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression, Cancer Res, vol.73, pp.2551-2562, 2013.

L. Chen, Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma, PloS One, vol.8, p.58413, 2013.

L. Lu, Klotho expression in epithelial ovarian cancer and its association with insulin-like growth factors and disease progression, Cancer Invest, vol.26, pp.185-192, 2008.

B. Chang, Klotho inhibits the capacity of cell migration and invasion in cervical cancer, Oncol. Rep, vol.28, pp.1022-1028, 2012.

X. Zhou, Klotho, an anti-aging gene, acts as a tumor suppressor and inhibitor of IGF-1R signaling in diffuse large B cell lymphoma, J. Hematol. Oncol.J Hematol Oncol, vol.10, p.37, 2017.

J. Usuda, Klotho is a novel biomarker for good survival in resected large cell neuroendocrine carcinoma of the lung, Lung Cancer Amst. Neth, vol.72, pp.355-359, 2011.

J. Usuda, Klotho predicts good clinical outcome in patients with limited-disease small cell lung cancer who received surgery, Lung Cancer Amst. Neth, vol.74, pp.332-337, 2011.

B. Chen, X. Wang, W. Zhao, and J. Wu, Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549, J. Exp. Clin. Cancer Res. CR, vol.29, p.99, 2010.

B. Chen, X. Ma, S. Liu, W. Zhao, and J. Wu, Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist, in a dose-dependent manner, Cancer Biol. Ther, vol.13, pp.1221-1228, 2012.

T. Chen, Decreased Level of Klotho Contributes to Drug Resistance in Lung Cancer Cells: Involving in Klotho-Mediated Cell Autophagy, DNA Cell Biol, vol.35, pp.751-757, 2016.

X. Wang, Combined effects of klotho and soluble CD40 ligand on A549 lung cancer cells, Oncol. Rep, vol.25, pp.1465-1472, 2011.

H. Sun, Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/?-catenin signaling pathway, World J. Surg. Oncol, vol.13, p.307, 2015.

G. Shu, Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells, Cell. Oncol. Dordr, vol.36, pp.121-129, 2013.

D. Dai, Klotho inhibits human follicular thyroid cancer cell growth and promotes apoptosis through regulation of the expression of stanniocalcin-1, Oncol. Rep, vol.35, pp.552-558, 2016.

Y. Wang, Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway, PloS One, vol.8, p.57391, 2013.

T. C. Camilli, Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility, Pigment Cell Melanoma Res, vol.24, pp.175-186, 2011.

A. Kasprzak, W. Kwasniewski, A. Adamek, and A. Gozdzicka-jozefiak, Insulin-like growth factor (IGF) axis in cancerogenesis, Mutat. Res. Mutat. Res, vol.772, pp.78-104, 2017.

D. Kasprowska-li?kiewicz, The cell on the edge of life and death: Crosstalk between autophagy and apoptosis, Postepy Hig. Med. Doswiadczalnej Online, vol.71, pp.825-841, 2017.

D. Danielpour and K. Song, Cross-talk between IGF-I and TGF-beta signaling pathways, Cytokine Growth Factor Rev, vol.17, pp.59-74, 2006.

T. Zhan, N. Rindtorff, and M. Boutros, Wnt signaling in cancer, Oncogene, vol.36, pp.1461-1473, 2017.

R. Behera, Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.23, pp.3181-3190, 2017.

L. M. Coussens and Z. Werb, Inflammation and cancer, Nature, vol.420, pp.860-867, 2002.

B. Qian, Inflammation fires up cancer metastasis, Semin. Cancer Biol, 2017.

A. R. Delbridge and A. Strasser, The BCL-2 protein family, BH3-mimetics and cancer therapy, Cell Death Differ, vol.22, pp.1071-1080, 2015.

B. Bonneau, J. Prudent, N. Popgeorgiev, and G. Gillet, Non-apoptotic roles of Bcl-2 family: the calcium connection, Biochim. Biophys. Acta, vol.1833, pp.1755-1765, 2013.

K. Yahata, Regulation of stanniocalcin 1 and 2 expression in the kidney by klotho gene, Biochem. Biophys. Res. Commun, vol.310, pp.128-134, 2003.

K. Fukino, Regulation of angiogenesis by the aging suppressor gene klotho, Biochem. Biophys. Res. Commun, vol.293, pp.332-337, 2002.

M. J. Berridge, M. D. Bootman, and P. Lipp, Calcium -a life and death signal, Nature, vol.395, pp.645-648, 1998.

M. J. Berridge, Inositol trisphosphate and calcium signalling mechanisms, Biochim. Biophys. Acta BBA -Mol. Cell Res, vol.1793, pp.933-940, 2009.

D. E. Clapham and . Signaling, Cell, vol.131, pp.1047-1058, 2007.

D. Prins and M. Michalak, Organellar calcium buffers, Cold Spring Harb. Perspect. Biol, vol.3, 2011.

R. Gomez-villafuertes, B. Mellström, and J. R. Naranjo, Searching for a role of NCX/NCKX exchangers in neurodegeneration, Mol. Neurobiol, vol.35, pp.195-202, 2007.

R. Balaji, Calcium spikes, waves and oscillations in a large, patterned epithelial tissue. Sci. Rep, vol.7, p.42786, 2017.

C. Lamont, P. W. Luther, C. W. Balke, and W. G. Wier, Intercellular Ca2+ waves in rat heart muscle, J. Physiol, vol.512, pp.669-676, 1998.

D. Wu, Y. Jia, X. Zhan, L. Yang, and Q. Liu, Effects of gap junction to Ca(2+) and to IP(3) on the synchronization of intercellular calcium oscillations in hepatocytes, Biophys. Chem, vol.113, pp.145-154, 2005.

S. Locovei, J. Wang, and G. Dahl, Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium, FEBS Lett, vol.580, pp.239-244, 2006.

W. A. Catterall, Voltage-Gated Calcium Channels, Cold Spring Harb. Perspect. Biol, vol.3, 2011.

A. Badou, M. K. Jha, D. Matza, and R. A. Flavell, Emerging Roles of L-Type Voltage-Gated and Other Calcium Channels in T Lymphocytes, Front. Immunol, vol.4, 2013.

K. Venkatachalam, C. Montell, and . Channels, Annu. Rev. Biochem, vol.76, pp.387-417, 2007.

A. Riccio, mRNA distribution analysis of human TRPC family in CNS and peripheral tissues, Mol. Brain Res, vol.109, pp.95-104, 2002.

M. Bishnoi, K. K. Kondepudi, A. Gupta, A. Karmase, and R. K. Boparai, Expression of multiple Transient Receptor Potential channel genes in murine 3T3-L1 cell lines and adipose tissue, Pharmacol. Rep. PR, vol.65, pp.751-755, 2013.

M. P. Winn, A Mutation in the TRPC6 Cation Channel Causes Familial Focal Segmental Glomerulosclerosis, Science, vol.308, pp.1801-1804, 2005.

J. Kim, Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes, J. Am. Soc. Nephrol. JASN, vol.28, pp.140-151, 2017.

L. Ambrus, Inhibition of TRPC6 by protein kinase C isoforms in cultured human podocytes, J. Cell. Mol. Med, vol.19, pp.2771-2779, 2015.

Y. Kwon, T. Hofmann, and C. Montell, Integration of Phosphoinositide-and Calmodulin-Mediated Regulation of TRPC6, Mol. Cell, vol.25, pp.491-503, 2007.

J. Shi, Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cells, J. Physiol, vol.561, pp.415-432, 2004.

C. Hisatsune, Regulation of TRPC6 channel activity by tyrosine phosphorylation, J. Biol. Chem, vol.279, pp.18887-18894, 2004.

T. Horinouchi, Adenylate cyclase/cAMP/protein kinase A signaling pathway inhibits endothelin type A receptor-operated Ca 2+ entry mediated via transient receptor potential canonical 6 channels, J. Pharmacol. Exp. Ther, vol.340, pp.143-151, 2012.

G. Hall, Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity, Am. J. Physiol. -Ren. Physiol, vol.306, pp.1442-1450, 2014.

A. Dietrich, N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity, J. Biol. Chem, vol.278, pp.47842-47852, 2003.

L. Albarrán, STIM1 regulates TRPC6 heteromultimerization and subcellular location, Biochem. J, vol.463, pp.373-381, 2014.

R. Ma, S. Chaudhari, and W. Li, Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology, Antioxid. Redox Signal, vol.25, pp.732-748, 2016.

Y. Li, Essential role of TRPC channels in the guidance of nerve growth cones by brainderived neurotrophic factor, Nature, vol.434, pp.894-898, 2005.

K. Kuwahara, TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling, J. Clin. Invest, vol.116, pp.3114-3126, 2006.

D. Tian, Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels, Sci. Signal, vol.3, p.77, 2010.

F. Van-petegem, Ryanodine Receptors: Structure and Function, J. Biol. Chem, vol.287, pp.31624-31632, 2012.

P. Koulen, Polycystin-2 is an intracellular calcium release channel, Nat. Cell Biol, vol.4, pp.191-197, 2002.

B. J. Wisnoskey, W. G. Sinkins, and W. P. Schilling, Activation of vanilloid receptor type I in the endoplasmic reticulum fails to activate store-operated Ca2+ entry, Biochem. J, vol.372, pp.517-528, 2003.

S. Thebault, Novel role of cold/menthol-sensitive transient receptor potential melastatine family member 8 (TRPM8) in the activation of store-operated channels in LNCaP human prostate cancer epithelial cells, J. Biol. Chem, vol.280, pp.39423-39435, 2005.
URL : https://hal.archives-ouvertes.fr/inserm-00137715

F. Van-coppenolle, Ribosome-translocon complex mediates calcium leakage from endoplasmic reticulum stores, J. Cell Sci, vol.117, pp.4135-4142, 2004.
URL : https://hal.archives-ouvertes.fr/inserm-00137717

N. Schäuble, BiP-mediated closing of the Sec61 channel limits Ca2+ leakage from the ER, EMBO J, vol.31, pp.3282-3296, 2012.

L. Verbert, Caspase-3-truncated type 1 inositol 1,4,5-trisphosphate receptor enhances intracellular Ca2+ leak and disturbs Ca2+ signalling, Biol. Cell, vol.100, pp.39-49, 2008.

F. Vanden-abeele, Functional implications of calcium permeability of the channel formed by pannexin 1, J. Cell Biol, vol.174, pp.535-546, 2006.

D. A. Lisak, The transmembrane Bax inhibitor motif (TMBIM) containing protein family: Tissue expression, intracellular localization and effects on the ER CA2+-filling state, Biochim. Biophys. Acta BBA -Mol. Cell Res, vol.1853, pp.2104-2114, 2015.

D. Rojas-rivera and C. Hetz, TMBIM protein family: ancestral regulators of cell death, Oncogene, vol.34, pp.269-280, 2015.

G. Bultynck, The C terminus of Bax inhibitor-1 forms a Ca2+-permeable channel pore, J. Biol. Chem, vol.287, pp.2544-2557, 2012.

T. Wegierski, TRPP2 channels regulate apoptosis through the Ca2+ concentration in the endoplasmic reticulum, EMBO J, vol.28, pp.490-499, 2009.

J. T. Smyth, Emerging perspectives in store-operated Ca2+ entry: Roles of Orai, Stim and TRP, Biochim. Biophys. Acta BBA -Mol. Cell Res, vol.1763, pp.1147-1160, 2006.

Y. Liao, Orai proteins interact with TRPC channels and confer responsiveness to store depletion, Proc. Natl. Acad. Sci. U. S. A, vol.104, pp.4682-4687, 2007.

N. Khadra, CD95 triggers Orai1-mediated localized Ca2+ entry, regulates recruitment of protein kinase C (PKC) ?2, and prevents death-inducing signaling complex formation, Proc. Natl. Acad. Sci. U. S. A, vol.108, pp.19072-19077, 2011.
URL : https://hal.archives-ouvertes.fr/inserm-00641268

P. Vacher, Localized Store-Operated Calcium Influx Represses CD95-Dependent Apoptotic Effects of Rituximab in Non-Hodgkin B Lymphomas, J. Immunol. Baltim. Md, pp.2207-2215, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01187410

R. E. Dolmetsch, R. S. Lewis, C. C. Goodnow, and J. I. Healy, Differential activation of transcription factors induced by Ca2+ response amplitude and duration, Nature, vol.386, pp.855-858, 1997.

R. J. Kaufman and J. D. Malhotra, Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics, Biochim. Biophys. Acta, vol.1843, pp.2233-2239, 2014.

T. Verfaillie, PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress, Cell Death Differ, vol.19, pp.1880-1891, 2012.

T. A. Stewart, K. T. Yapa, and G. R. Monteith, Altered calcium signaling in cancer cells, Biochim. Biophys. Acta BBA -Biomembr, vol.1848, pp.2502-2511, 2015.

A. Fiorio-pla, K. Kondratska, and N. Prevarskaya, STIM and ORAI proteins: crucial roles in hallmarks of cancer, Am. J. Physiol. Cell Physiol, vol.310, pp.509-519, 2016.

V. Lehen'kyi and N. Prevarskaya, Oncogenic TRP channels, Adv. Exp. Med. Biol, vol.704, pp.929-945, 2011.

Y. Chen, Y. Chen, W. Chiu, and M. Shen, Remodeling of calcium signaling in tumor progression, J. Biomed. Sci, vol.20, p.23, 2013.

N. Prevarskaya, R. Skryma, and Y. Shuba, Calcium in tumour metastasis: new roles for known actors, Nat. Rev. Cancer, vol.11, pp.609-618, 2011.

G. Shapovalov, A. Ritaine, R. Skryma, and N. Prevarskaya, Role of TRP ion channels in cancer and tumorigenesis, Semin. Immunopathol, vol.38, pp.357-369, 2016.

J. M. Lee, F. M. Davis, S. J. Roberts-thomson, and G. R. Monteith, Ion channels and transporters in cancer. 4. Remodeling of Ca(2+) signaling in tumorigenesis: role of Ca(2+) transport, Am. J. Physiol. Cell Physiol, vol.301, pp.969-976, 2011.

V. Lehen'kyi, M. Flourakis, R. Skryma, and N. Prevarskaya, TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways, Oncogene, vol.26, pp.7380-7385, 2007.

T. Fixemer, U. Wissenbach, V. Flockerzi, and H. Bonkhoff, Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression, Oncogene, vol.22, pp.7858-7861, 2003.

M. Faouzi, Down-regulation of Orai3 arrests cell-cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells, J. Cell. Physiol, vol.226, pp.542-551, 2011.

M. Faouzi, ORAI3 silencing alters cell proliferation and cell cycle progression via c-myc pathway in breast cancer cells, Biochim. Biophys. Acta, vol.1833, pp.752-760, 2013.

K. Tiedemann, Breast Cancer-derived Factors Stimulate Osteoclastogenesis through the Ca2+/Protein Kinase C and Transforming Growth Factor-?/MAPK Signaling Pathways, J. Biol. Chem, vol.284, pp.33662-33670, 2009.

D. Jaquemar, T. Schenker, and B. Trueb, An ankyrin-like protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts, J. Biol. Chem, vol.274, pp.7325-7333, 1999.

L. Wang, Targeting Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase 2 by Curcumin Induces ER Stress-Associated Apoptosis for Treating Human Liposarcoma, Mol. Cancer Ther, vol.10, pp.461-471, 2011.

L. Wang, High expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2b blocks cell differentiation in human liposarcoma cells, Life Sci, vol.99, pp.37-43, 2014.

M. Hisaoka, A. Matsuyama, and M. Nakamoto, Aberrant calreticulin expression is involved in the dedifferentiation of dedifferentiated liposarcoma, Am. J. Pathol, vol.180, pp.2076-2083, 2012.

N. Bell, V. Hann, C. P. Redfern, and T. R. Cheek, Store-operated Ca2+ entry in proliferating and retinoic acid-differentiated N-and S-type neuroblastoma cells, Biochim. Biophys. Acta BBA -Mol. Cell Res, vol.1833, pp.643-651, 2013.

Y. M. Usachev, S. L. Toutenhoofd, G. M. Goellner, E. E. Strehler, and S. A. Thayer, Differentiation induces up-regulation of plasma membrane Ca2+-ATPase and concomitant increase in Ca2+ efflux in human neuroblastoma cell line IMR-32, J. Neurochem, vol.76, pp.1756-1765, 2001.

K. Varga, Histone deacetylase inhibitor-and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells, Cell Calcium, vol.55, pp.78-92, 2014.

W. J. Lee, S. J. Roberts-thomson, and G. R. Monteith, Plasma membrane calcium-ATPase 2 and 4 in human breast cancer cell lines, Biochem. Biophys. Res. Commun, vol.337, pp.779-783, 2005.

P. Ribiczey, Isoform-specific up-regulation of plasma membrane Ca2+ATPase expression during colon and gastric cancer cell differentiation, Cell Calcium, vol.42, pp.590-605, 2007.

A. Arbabian, Modulation of endoplasmic reticulum calcium pump expression during lung cancer cell differentiation, FEBS J, vol.280, pp.5408-5418, 2013.

N. Prevarskaya, H. Ouadid-ahidouch, R. Skryma, and Y. Shuba, Remodelling of Ca2+ transport in cancer: how it contributes to cancer hallmarks?, Philos. Trans. R. Soc. B Biol. Sci, vol.369, 2014.

C. White, The Regulation of Tumor Cell Invasion and Metastasis by Endoplasmic Reticulumto-Mitochondrial Ca(2+) Transfer. Front, Oncol, vol.7, p.171, 2017.

A. Fouqué, The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca(2+) flux from the endoplasmic reticulum to mitochondria, Cell Death Differ, vol.23, pp.1702-1716, 2016.

L. Pazzaglia, Activation of Metalloproteinases-2 and -9 by Interleukin-1? in S100A4-positive Liposarcoma Cell Line: Correlation with Cell Invasiveness, Anticancer Res, vol.24, pp.967-972, 2004.

K. Vanoverberghe, Ca2+ homeostasis and apoptotic resistance of neuroendocrinedifferentiated prostate cancer cells, Cell Death Differ, vol.11, pp.321-330, 2004.

M. Flourakis, Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells, Cell Death Dis, vol.1, p.75, 2010.
URL : https://hal.archives-ouvertes.fr/inserm-00520275

A. Safa, A. R.-c-flip, and . Master-anti-apoptotic-regulator, Exp. Oncol, vol.34, pp.176-184, 2012.

E. C. Toescu, Hypoxia sensing and pathways of cytosolic Ca2+ increases, Cell Calcium, vol.36, pp.187-199, 2004.

S. Li, Crucial role of TRPC6 in maintaining the stability of HIF-1? in glioma cells under hypoxia, J. Cell Sci, vol.128, pp.3317-3329, 2015.

M. Raphaël, TRPV6 calcium channel translocates to the plasma membrane via Orai1-mediated mechanism and controls cancer cell survival, Proc. Natl. Acad. Sci. U. S. A, vol.111, pp.3870-3879, 2014.

E. A. Schaefer, Stimulation of the chemosensory TRPA1 cation channel by volatile toxic substances promotes cell survival of small cell lung cancer cells, Biochem. Pharmacol, vol.85, pp.426-438, 2013.

A. Bergner, J. Kellner, A. Tufman, and R. M. Huber, Endoplasmic reticulum Ca2+-homeostasis is altered in Small and non-small Cell Lung Cancer cell lines, J. Exp. Clin. Cancer Res. CR, vol.28, p.25, 2009.

S. Padar, Differential regulation of calcium homeostasis in adenocarcinoma cell line A549 and its Taxol-resistant subclone, Br. J. Pharmacol, vol.142, pp.305-316, 2004.

G. Colotti, Sorcin, a calcium binding protein involved in the multidrug resistance mechanisms in cancer cells, Mol. Basel Switz, vol.19, pp.13976-13989, 2014.

J. B. Gifford and R. Hill, GRP78 Influences Chemoresistance and Prognosis in Cancer, Curr. Drug Targets, 2017.

M. Y. Stoeckle, 78-kilodalton glucose-regulated protein is induced in Rous sarcoma virus-transformed cells independently of glucose deprivation, Mol. Cell. Biol, vol.8, pp.2675-2680, 1988.

Y. Rong, Targeting Bcl-2-IP3 Receptor Interaction to Reverse Bcl-2's Inhibition of Apoptotic Calcium Signals, Mol. Cell, vol.31, pp.255-265, 2008.

X. Sui, Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment, Cell Death Dis, vol.4, p.838, 2013.

M. D. Bootman, T. Chehab, G. Bultynck, J. B. Parys, and K. Rietdorf, The regulation of autophagy by calcium signals: Do we have a consensus? Cell Calcium, 2017.

F. Lodola, Store-operated Ca2+ entry is remodelled and controls in vitro angiogenesis in endothelial progenitor cells isolated from tumoral patients, PloS One, vol.7, p.42541, 2012.

A. Fiorio-pla, TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling, Oncogene, vol.31, pp.200-212, 2012.

N. Rivlin, R. Brosh, M. Oren, and V. Rotter, Mutations in the p53 Tumor Suppressor Gene, Genes Cancer, vol.2, pp.466-474, 2011.

V. Farfariello, O. Iamshanova, E. Germain, I. Fliniaux, and N. Prevarskaya, Calcium homeostasis in cancer: A focus on senescence, Biochim. Biophys. Acta, vol.1853, p.260, 2015.

A. Matte, M. Y. Moses-soto, H. Kruk, and P. A. , Calcium-mediated telomerase activity in ovarian epithelial cells, Arch. Biochem. Biophys, vol.399, pp.239-244, 2002.

S. Rosenberger, I. S. Thorey, S. Werner, and P. Boukamp, A novel regulator of telomerase. S100A8 mediates differentiation-dependent and calcium-induced inhibition of telomerase activity in the human epidermal keratinocyte line HaCaT, J. Biol. Chem, vol.282, pp.6126-6135, 2007.

J. Lin, Inhibition of p53 transcriptional activity by the S100B calcium-binding protein, J. Biol. Chem, vol.276, pp.35037-35041, 2001.

A. Mueller, The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity, J. Biol. Chem, vol.280, pp.29186-29193, 2005.

C. Wiel, Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence, Nat. Commun, vol.5, p.3792, 2014.

J. Coppé, P. Desprez, A. Krtolica, and J. Campisi, The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression, Annu. Rev. Pathol, vol.5, pp.99-118, 2010.

R. R. Gordon and P. S. Nelson, Cellular Senescence and Cancer Chemotherapy Resistance, Drug Resist. Updat, vol.15, pp.123-131, 2012.

J. Sage, A. L. Miller, P. A. Pérez-mancera, J. M. Wysocki, and T. Jacks, Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry, Nature, vol.424, pp.223-228, 2003.

T. L. Whiteside, The tumor microenvironment and its role in promoting tumor growth, Oncogene, vol.27, pp.5904-5912, 2008.

J. Galon, Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome, Science, vol.313, pp.1960-1964, 2006.

B. Sharma, S. S. Kanwar, and . Phosphatidylserine, A cancer cell targeting biomarker. Semin. Cancer Biol, 2017.

S. D. Vallabhapurapu, Variation in human cancer cell external phosphatidylserine is regulated by flippase activity and intracellular calcium, Oncotarget, vol.6, pp.34375-34388, 2015.

V. R. Wiersma, M. Michalak, T. M. Abdullah, E. Bremer, and P. Eggleton, Mechanisms of Translocation of ER Chaperones to the Cell Surface and Immunomodulatory Roles in Cancer and, Autoimmunity. Front. Oncol, vol.5, p.7, 2015.

A. D. Garg, Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation, Biochim. Biophys. Acta, vol.1805, pp.53-71, 2010.

T. Panaretakis, Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death, EMBO J, vol.28, pp.578-590, 2009.

O. Kepp, Crosstalk between ER stress and immunogenic cell death, Cytokine Growth Factor Rev, vol.24, pp.311-318, 2013.

, Stable Instability of Sarcoma Cell Lines Genome Despite Intra-Tumoral Heterogeneity: A Genomic and Transcriptomic Study of Sarcoma Cell Lines

, Stable Instability of Sarcoma Cell Lines Genome Despite Intra-Tumoral Heterogeneity: A Genomic and Transcriptomic Study of Sarcoma Cell Lines, p.11, 2016.

M. Trebak, G. Vazquez, G. S. Bird, and J. W. Putney, The TRPC3/6/7 subfamily of cation channels, Cell Calcium, vol.33, pp.451-461, 2003.

C. Wang, Thapsigargin induces apoptosis when autophagy is inhibited in HepG2 cells and both processes are regulated by ROS-dependent pathway, Environ. Toxicol. Pharmacol, vol.41, pp.167-179, 2016.

P. T. Schumacker, Reactive Oxygen Species in Cancer: A Dance with the Devil, Cancer Cell, vol.27, pp.156-157, 2015.

S. Arora, An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through reactive oxygen species-dependent, nuclear factor ?B-and hypoxia-inducible factor 1?-mediated up-regulation of CXCR4, J. Biol. Chem, vol.288, pp.21197-21207, 2013.

S. Chakradeo, L. W. Elmore, and D. A. Gewirtz, Is Senescence Reversible?, Curr. Drug Targets, vol.17, pp.460-466, 2016.

K. Kondratska, Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma, Biochim. Biophys. Acta, vol.1843, pp.2263-2269, 2014.

M. T. Harper and A. W. Poole, Bcl-xL-inhibitory BH3 mimetic ABT-737 depletes platelet calcium stores, Blood, vol.119, pp.4337-4338, 2012.

V. Casas-rua, STIM1 phosphorylation triggered by epidermal growth factor mediates cell migration, Biochim. Biophys. Acta BBA -Mol. Cell Res, vol.1853, pp.233-243, 2015.

F. Erdmann, Interaction of calmodulin with Sec61? limits Ca2+ leakage from the endoplasmic reticulum, EMBO J, vol.30, pp.17-31, 2011.

E. Friedlova, The interactions of the C-terminal region of the TRPC6 channel with calmodulin, Neurochem. Int, vol.56, pp.363-366, 2010.

P. Chaudhuri, Membrane translocation of TRPC6 channels and endothelial migration are regulated by calmodulin and PI3 kinase activation, Proc. Natl. Acad. Sci. U. S. A, vol.113, pp.2110-2115, 2016.

N. Agell, O. Bachs, N. Rocamora, and P. Villalonga, Modulation of the Ras/Raf/MEK/ERK pathway by Ca(2+), and calmodulin, Cell. Signal, vol.14, pp.649-654, 2002.

R. Dai, R. Chen, and H. Li, Cross-talk between PI3K/Akt and MEK/ERK pathways mediates endoplasmic reticulum stress-induced cell cycle progression and cell death in human hepatocellular carcinoma cells, Int. J. Oncol, vol.34, pp.1749-1757, 2009.

C. C. Jiang, Inhibition of MEK sensitizes human melanoma cells to endoplasmic reticulum stress-induced apoptosis, Cancer Res, vol.67, pp.9750-9761, 2007.

C. C. Jiang, Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress, Cancer Res, vol.68, pp.6708-6717, 2008.

M. Yun, S. Kim, S. H. Jeon, J. Lee, and K. Choi, Both ERK and Wnt/beta-catenin pathways are involved in Wnt3a-induced proliferation, J. Cell Sci, vol.118, pp.313-322, 2005.

D. Chuderland and R. Seger, Calcium regulates ERK signaling by modulating its protein-protein interactions, Commun. Integr. Biol, vol.1, pp.4-5, 2008.

Y. Son, S. Kim, H. Chung, H. Pae, and . Chapter, Reactive Oxygen Species in the Activation of MAP Kinases. in Methods in Enzymology, vol.528, pp.27-48, 2013.

A. Plotnikov, E. Zehorai, S. Procaccia, and R. Seger, The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation, Biochim. Biophys. Acta BBA -Mol. Cell Res, vol.1813, pp.1619-1633, 2011.

C. Tse, ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor, Cancer Res, vol.68, pp.3421-3428, 2008.

D. M. Aresvik, R. D. Pettersen, T. G. Abrahamsen, and M. S. Wright, 5-Fluorouracil-induced Death of Jurkat T-Cells -A Role for Caspases and MCL-1, Anticancer Res, vol.30, pp.3879-3887, 2010.

J. M. Cleary, A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors, Invest. New Drugs, vol.32, pp.937-945, 2014.

I. Okuda, A large calcified retroperitoneal mass in a patient with chronic renal failure: liposarcoma with ossification, Clin. Exp. Nephrol, vol.14, pp.185-189, 2010.

M. Lai, Giant bilateral perinephric tumour and overt proteinuria, Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. -Eur. Ren. Assoc, vol.22, pp.2089-2090, 2007.

H. G. Skinner and G. G. Schwartz, Serum calcium and incident and fatal prostate cancer in the National Health and Nutrition Examination Survey, Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol, vol.17, pp.2302-2305, 2008.

H. G. Skinner and G. G. Schwartz, A Prospective Study of Total and Ionized Serum Calcium and Fatal Prostate Cancer, Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol, vol.18, pp.575-578, 2009.

H. Shi, Y. D. Halvorsen, P. N. Ellis, W. O. Wilkison, and M. B. Zemel, Role of intracellular calcium in human adipocyte differentiation, Physiol. Genomics, vol.3, pp.75-82, 2000.

D. Mahalingam, Mipsagargin, a novel thapsigargin-based PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with refractory, advanced or metastatic solid tumours, Br. J. Cancer, vol.114, pp.986-994, 2016.

B. Heitkötter, Expression of PSMA in tumor neovasculature of high grade sarcomas including synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma and MPNST, Oncotarget, vol.8, pp.4268-4276, 2016.

A. Wozniak, Abstract 5197: Patient-derived xenograft (PDX) models of soft tissue sarcoma (STS): a preclinical platform for early drug testing, Cancer Res, vol.76, pp.5197-5197, 2016.

L. Ireland, Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors, Cancer Res, vol.76, pp.6851-6863, 2016.

J. C. De-freitas-junior, J. Andrade-da-costa, M. C. Silva, and S. S. Pinho, Glycans as Regulatory Elements of the Insulin/IGF System: Impact in Cancer Progression, Int. J. Mol. Sci, vol.18, p.1921, 2017.

S. S. Pinho and C. A. Reis, Glycosylation in cancer: mechanisms and clinical implications, Nat. Rev. Cancer, vol.15, p.3982, 2015.

S. Benzekry, A. Beheshti, P. Hahnfeldt, and L. Hlatky, Capturing the Driving Role of Tumor-Host Crosstalk in a Dynamical Model of Tumor Growth, Bio-Protoc, vol.5, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01222068

E. Baratchart, Computational Modelling of Metastasis Development in Renal Cell Carcinoma, PLoS Comput. Biol, vol.11, p.1004626, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01164834

X. Sun, J. Bao, and Y. Shao, Mathematical Modeling of Therapy-induced Cancer Drug Resistance: Connecting Cancer Mechanisms to Population Survival Rates, Sci. Rep, vol.6, 2016.

J. Ciccolini, S. Benzekry, B. Lacarelle, D. Barbolosi, and F. Barlési, Improving efficacy of the combination between antiangiogenic and chemotherapy: Time for mathematical modeling support, Proc. Natl. Acad. Sci. U. S. A, vol.112, p.3453, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01168635

R. Serre, Mathematical Modeling of Cancer Immunotherapy and Its Synergy with Radiotherapy, Cancer Res, vol.76, pp.4931-4940, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01336779

C. Angermueller, T. Pärnamaa, L. Parts, and O. Stegle, Deep learning for computational biology, Mol. Syst. Biol, vol.12, 2016.

W. Muhlestein, Using a Novel Machine Learning Technique to Predict Brain Metastasis Velocity Following Stereotactic Radiosurgery for Brain Metastases, Int. J. Radiat. Oncol, vol.99, p.96, 2017.

, To reconstitute Bclx-silenced BT549 cells with our BclxL constructs, shRNA-BclxL-expressing cells were transfected by electroporation with pcDNA3 vector encoding BclxL-WT, BclxL-Acta (MT) or BclxL-CytB5 (ER) or empty vector. Twenty-four hours after transfection, cells were placed in a medium supplemented with 0.6 mg/ml of neomycin. Neomycin-resistant colonies were isolated using cloning cylinders, Then, cells stably expressing shRNA were selected for 7 days using 0.5 ?g/ml of puromycin

P. Antibodies and . Reagents, Anti-BclxL, anti-Bcl-2, anti-Akt, anti-phosphoS473 Akt, anti-phosphoThr308 Akt, and anti-BAD were from, Anti-CD95 (C20), anti-VDAC1, and Ru360 were purchased from Santa Cruz

, These peptides were coupled with the cell-permeant sequence of antennapedia homeodomain (RQIKIWFQNRRMKWKK) to their C-terminal domain. IgCD95L and metalloprotease-cleaved CD95L were generated in the laboratory, N-terminal peptide (LGKSARDVFTKGYGFG) and L14-15 peptide, vol.12

, FuraPE3 and Fluo2-AM were from Euromedex

;. and B. Sigma, GFP sequence lacking stop codon was amplified by PCR from pEGFPN1 sequence using primer pair: sense CGGGATCCATGGTGAGCAAGGGCGAGGAG CTG and antisense CCGCTCGAGCTTGTACAGCTCGTCCATGCCG. The amplicons was digested by Xho1 and BamH1 and inserted into Xho1 and BamH1-cleaved pcDNA3.1(+). Next, pcDNA3.1(+)-GFP was linearized using XhoI/XbaI and sequences corresponding to amino acid residues 107-142 of human CytB5 (ITTIDSSSSWWTNWVIPAISAVAVALMYRLYMAED) or residues 613-639 of Acta, mitotracker green and Rhod2-AM were from Life Technologies SAS

E. H. Cheng, M. C. Wei, S. Weiler, R. A. Flavell, T. W. Mak et al., BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis, Mol Cell, vol.8, pp.705-711, 2001.

G. Monaco, T. Vervliet, H. Akl, and G. Bultynck, The selective BH4-domain biology of Bcl-2-family members: IP3Rs and beyond, Cell Mol Life Sci, vol.70, pp.1171-1183, 2013.

Y. C. Du, B. C. Lewis, D. Hanahan, and H. Varmus, Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion, PLoS Biol, vol.5, p.276, 2007.

J. H. Hager, D. B. Ulanet, L. Hennighausen, and D. Hanahan, Genetic ablation of Bcl-x attenuates invasiveness without affecting apoptosis or tumor growth in a mouse model of pancreatic neuroendocrine cancer, PLoS One, vol.4, p.4455, 2009.

S. S. Martin, A. G. Ridgeway, J. Pinkas, Y. Lu, M. J. Reginato et al., A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth, Oncogene, vol.23, pp.4641-4645, 2004.

G. H. Fisher, F. J. Rosenberg, S. E. Straus, J. K. Dale, L. A. Middleton et al., Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome, Cell, vol.81, pp.935-946, 1995.

F. Rieux-laucat, L. Deist, F. Hivroz, C. Roberts, I. A. Debatin et al., Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity, Science, vol.268, pp.1347-1349, 1995.

J. Drappa, A. K. Vaishnaw, K. E. Sullivan, J. L. Chu, and K. B. Elkon, Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity, N Engl J Med, vol.335, pp.1643-1649, 1996.

A. Strasser, P. J. Jost, and S. Nagata, The many roles of FAS receptor signaling in the immune system, Immunity, vol.30, pp.180-192, 2009.

S. Tauzin, L. Debure, J. F. Moreau, and P. Legembre, CD95-mediated cell signaling in cancer: mutations and post-translational modulations, Cell Mol Life Sci, vol.69, pp.1261-1277, 2012.
URL : https://hal.archives-ouvertes.fr/hal-00682466

L. A. O'-reilly, L. Tai, L. Lee, E. A. Kruse, S. Grabow et al., Membrane-bound Fas ligand only is essential for Fas-induced apoptosis, Nature, vol.461, pp.659-663, 2009.

S. Tauzin, B. Chaigne-delalande, E. Selva, N. Khadra, S. Daburon et al., The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway, PLoS Biol, vol.9, p.1001090, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00681970

F. J. Hoogwater, M. W. Nijkamp, N. Smakman, E. J. Steller, B. L. Emmink et al., Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells, Gastroenterology, vol.138, pp.2357-2367, 2010.

S. Kleber, I. Sancho-martinez, B. Wiestler, A. Beisel, C. Gieffers et al., Yes and PI3K bind CD95 to signal invasion of glioblastoma, Cancer Cell, vol.13, pp.235-248, 2008.

M. Malleter, S. Tauzin, A. Bessede, R. Castellano, A. Goubard et al., CD95L cell surface cleavage triggers a prometastatic signaling pathway in triple-negative breast cancer, Cancer Res, vol.73, pp.6711-6721, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00873634

M. E. Peter, A. Hadji, A. E. Murmann, S. Brockway, W. Putzbach et al., The role of CD95 and CD95 ligand in cancer, Cell Death Differ, vol.22, pp.549-559, 2015.

R. Dent, M. Trudeau, K. I. Pritchard, W. M. Hanna, H. K. Kahn et al., Triple-negative breast cancer: clinical features and patterns of recurrence, Clin Cancer Res, vol.13, issue.15, pp.4429-4434, 2007.

L. A. Carey, E. C. Dees, L. Sawyer, L. Gatti, D. T. Moore et al., The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes, Clin Cancer Res, vol.13, pp.2329-2334, 2007.

D. Hanahan and R. A. Weinberg, Hallmarks of cancer: the next generation, Cell, vol.144, pp.646-674, 2011.

T. Oltersdorf, S. W. Elmore, A. R. Shoemaker, R. C. Armstrong, D. J. Augeri et al., An inhibitor of Bcl-2 family proteins induces regression of solid tumours, Nature, vol.435, pp.677-681, 2005.

S. Kharbanda, P. Pandey, L. Schofield, S. Israels, R. Roncinske et al., Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis, Proc Natl Acad Sci, vol.94, pp.6939-6942, 1997.

R. M. Kluck, E. Bossy-wetzel, D. R. Green, and D. D. Newmeyer, The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis, Science, vol.275, pp.1132-1136, 1997.

J. Yang, X. Liu, K. Bhalla, C. N. Kim, A. M. Ibrado et al., Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked, Science, vol.275, pp.1129-1132, 1997.

S. Krajewski, S. Tanaka, S. Takayama, M. J. Schibler, W. Fenton et al., Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes, Cancer Res, vol.53, pp.4701-4714, 1993.

W. Zhu, A. Cowie, G. W. Wasfy, L. Z. Penn, B. Leber et al., Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types, EMBO J, vol.15, pp.4130-4141, 1996.

A. J. Souers, J. D. Leverson, E. R. Boghaert, S. L. Ackler, N. D. Catron et al., ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets, Nat Med, vol.19, pp.202-208, 2013.

J. A. Gilabert and A. B. Parekh, Respiring mitochondria determine the pattern of activation and inactivation of the store-operated Ca(2+) current I(CRAC), EMBO J, vol.19, pp.6401-6407, 2000.

E. Yang, J. Zha, J. Jockel, L. H. Boise, C. B. Thompson et al., Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death, Cell, vol.80, pp.285-291, 1995.

N. N. Danial, L. D. Walensky, C. Y. Zhang, C. S. Choi, J. K. Fisher et al., Dual role of proapoptotic BAD in insulin secretion and beta cell survival, Nat Med, vol.14, pp.144-153, 2008.

S. R. Datta, H. Dudek, X. Tao, S. Masters, H. Fu et al., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery, Cell, vol.91, pp.231-241, 1997.

L. Del-peso, M. Gonzalez-garcia, C. Page, R. Herrera, and G. Nunez, Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt, Science, vol.278, pp.687-689, 1997.

H. Li, H. Zhu, C. J. Xu, and J. Yuan, Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis, Cell, vol.94, pp.491-501, 1998.

X. Luo, I. Budihardjo, H. Zou, C. Slaughter, and X. Wang, Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors, Cell, vol.94, pp.481-490, 1998.

S. Daburon, C. Devaud, P. Costet, A. Morello, L. Garrigue-antar et al., Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity, PLoS One, vol.8, p.54000, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00873684

H. Huang, X. Hu, C. O. Eno, G. Zhao, C. Li et al., An interaction between Bcl-xL and the voltage-dependent anion channel (VDAC) promotes mitochondrial Ca2+ uptake, J Biol Chem, vol.288, pp.19870-19881, 2013.

E. Rapizzi, P. Pinton, G. Szabadkai, M. R. Wieckowski, G. Vandecasteele et al., Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria, J Cell Biol, vol.159, pp.613-624, 2002.

D. Stefani, D. Raffaello, A. Teardo, E. Szabo, I. Rizzuto et al., A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter, Nature, vol.476, pp.336-340, 2011.

J. M. Baughman, F. Perocchi, H. S. Girgis, M. Plovanich, C. A. Belcher-timme et al., Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter, Nature, vol.476, pp.341-345, 2011.

J. Q. Kwong, X. Lu, R. N. Correll, J. A. Schwanekamp, R. J. Vagnozzi et al., The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart, Cell Rep, vol.12, pp.15-22, 2015.

C. Cardenas, R. A. Miller, I. Smith, T. Bui, J. Molgo et al., Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria, Cell, vol.142, pp.270-283, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00506136

M. S. Patel and L. G. Korotchkina, Regulation of the pyruvate dehydrogenase complex, Biochem Soc Trans, vol.34, issue.2, pp.217-222, 2006.

N. Khadra, L. Bresson-bepoldin, A. Penna, B. Chaigne-delalande, B. Segui et al., CD95 triggers Orai1-mediated localized Ca2+ entry, regulates recruitment of protein kinase C (PKC) beta2, and prevents death-inducing signaling complex formation, Proc Natl Acad Sci, vol.108, pp.19072-19077, 2011.

G. Monaco, E. Decrock, H. Akl, R. Ponsaerts, T. Vervliet et al., Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl, Cell Death Differ, vol.19, pp.295-309, 2012.

C. U. Choe and B. E. Ehrlich, The inositol 1,4,5-trisphosphate receptor (IP3R) and its regulators: sometimes good and sometimes bad teamwork, Sci STKE, p.15, 2006.

B. C. Barnhart, P. Legembre, E. Pietras, C. Bubici, G. Franzoso et al., CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells, Embo J, vol.23, pp.3175-3185, 2004.

L. Chen, S. M. Park, A. V. Tumanov, A. Hau, K. Sawada et al., CD95 promotes tumour growth, Nature, vol.465, pp.492-496, 2010.

C. Wei, X. Wang, M. Chen, K. Ouyang, L. S. Song et al., Calcium flickers steer cell migration, Nature, vol.457, pp.901-905, 2009.

P. Pinton, C. Giorgi, and P. P. Pandolfi, The role of PML in the control of apoptotic cell fate: a new key player at ER-mitochondria sites, Cell Death Differ, vol.18, pp.1450-1456, 2011.

J. Tuettenberg, M. Seiz, K. M. Debatin, W. Hollburg, M. Von-staden et al., Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients, Int Immunopharmacol, vol.13, pp.93-100, 2012.

C. Tse, A. R. Shoemaker, J. Adickes, M. G. Anderson, J. Chen et al., ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor, Cancer Res, vol.68, pp.3421-3428, 2008.

C. M. Rudin, C. L. Hann, E. B. Garon, R. De-oliveira, M. Bonomi et al., Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer, Clin Cancer Res, vol.18, pp.3163-3169, 2012.

S. M. Schoenwaelder and S. P. Jackson, Bcl-xL-inhibitory BH3 mimetics (ABT-737 or ABT-263) and the modulation of cytosolic calcium flux and platelet function, Blood, vol.119, pp.1321-1322, 2012.

C. O. Eno, E. F. Eckenrode, K. E. Olberding, G. Zhao, C. White et al., Distinct roles of mitochondriaand ER-localized Bcl-xL in apoptosis resistance and Ca2+ homeostasis, Mol Biol Cell, vol.23, pp.2605-2618, 2012.

B. Chaigne-delalande, W. Mahfouf, S. Daburon, J. F. Moreau, and P. Legembre, CD95 engagement mediates actin-independent and -dependent apoptotic signals, Cell Death Differ, vol.16, pp.1654-1664, 2009.

C. Vorndran, A. Minta, and M. Poenie, New fluorescent calcium indicators designed for cytosolic retention or measuring calcium near membranes, Biophys J, vol.69, pp.2112-2124, 1995.

H. Imamura, K. P. Nhat, H. Togawa, K. Saito, R. Iino et al., Visualization of ATP levels inside single living cells with fluorescence resonance energy transfer-based genetically encoded indicators, Proc Natl Acad Sci, vol.106, pp.15651-15656, 2009.

, Calcium Release-Activated Calcium channels. ER, Endoplasmic Reticulum. IP 3 , Inositol 1,4,5-tris-Phosphate. IP 3 R, IP 3 Receptors. MCU, Mitochondrial Calcium Uniporter. PLC, PhosphoLipase C. PTP, Permeability Transition Pore. SERCA, Sarcoplasmic/Endoplasmic Reticulum Ca 2+ -ATPase, CRAC channels

. Soce, Store-Operated Calcium Entry. SSRI, Selective Serotonin Re-uptake Inhibitor

D. T. Wong, F. P. Bymaster, and E. A. Engleman, Prozac (fluoxetine, lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication, Life Sciences, vol.57, pp.411-441, 1995.

C. Hiemke and S. Hartter, Pharmacokinetics of selective serotonin reuptake inhibitors, Pharmacol Ther, vol.85, pp.11-28, 2000.

Y. Levkovitz, I. Gil-ad, E. Zeldich, M. Dayag, and A. Weizman, Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for p-c-Jun, cytochrome c, and caspase-3 involvement, J Mol Neurosci, vol.27, pp.29-42, 2005.

A. Stepulak, W. Rzeski, M. Sifringer, K. Brocke, A. Gratopp et al., Fluoxetine inhibits the extracellular signal regulated kinase pathway and suppresses growth of cancer cells, Cancer Biol Ther, vol.7, pp.1685-1693, 2008.

M. Abdul, C. J. Logothetis, and N. M. Hoosein, Growthinhibitory effects of serotonin uptake inhibitors on human prostate carcinoma cell lines, J Urol, vol.154, pp.247-250, 1995.

H. Arimochi and K. Morita, Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells, Eur J Pharmacol, vol.541, pp.17-23, 2006.

A. Krishnan, R. Hariharan, S. A. Nair, and M. R. Pillai, Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS), p.1

, Biochem Pharmacol, vol.75, pp.1924-1934, 2008.

C. S. Lee, Y. J. Kim, E. R. Jang, K. W. , and M. Sc, Fluoxetine induces apoptosis in ovarian carcinoma cell line OVCAR-3 through reactive oxygen species-dependent activation of nuclear factor-kappaB, Basic Clin Pharmacol Toxicol, vol.106, pp.446-453, 2010.

A. Serafeim, M. J. Holder, G. Grafton, A. Chamba, M. T. Drayson et al., Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells, Blood, vol.101, pp.3212-3219, 2003.

S. M. Cloonan, A. Drozgowska, D. Fayne, and D. C. Williams, The antidepressants maprotiline and fluoxetine have potent selective antiproliferative effects against Burkitt lymphoma independently of the norepinephrine and serotonin transporters, Leuk Lymphoma, vol.51, pp.523-539, 2010.

A. R. Mun, S. J. Lee, G. B. Kim, H. S. Kang, J. S. Kim et al., Fluoxetine-induced apoptosis in hepatocellular carcinoma cells, Anticancer Res, vol.33, pp.3691-3697, 2013.

P. J. Tutton and D. H. Barkla, Influence of inhibitors of serotonin uptake on intestinal epithelium and colorectal carcinomas, Br J Cancer, vol.46, pp.260-265, 1982.

S. J. Koh, J. M. Kim, I. K. Kim, N. Kim, H. C. Jung et al., Fluoxetine inhibits NF-kappaB signaling in intestinal epithelial cells and ameliorates experimental colitis and colitis-associated colon cancer in mice, Am J Physiol Gastrointest Liver Physiol, vol.301, pp.9-19, 2011.

B. Grygier, B. Arteta, M. Kubera, A. Basta-kaim, B. Budziszewska et al., Inhibitory effect of antidepressants on B16F10 melanoma tumor growth, Pharmacol Rep, vol.65, pp.672-681, 2013.

V. A. Edgar, A. M. Genaro, G. Cremaschi, and L. Sterin-borda, Fluoxetine action on murine T-lymphocyte proliferation: participation of PKC activation and calcium mobilisation, Cell Signal, vol.10, pp.721-726, 1998.

V. A. Edgar, L. Sterin-borda, C. Ga, and A. M. Genaro, Role of protein kinase C and cAMP in fluoxetine effects on human T-cell proliferation, Eur J Pharmacol, vol.372, pp.65-73, 1999.

A. M. Genaro, E. Va, and L. Sterin-borda, Differential effects of fluoxetine on murine B-cell proliferation depending on the biochemical pathways triggered by distinct mitogens, Biochem Pharmacol, vol.60, pp.1279-1283, 2000.

N. D. Slamon, C. Mead, C. Morgan, M. A. Pentreath, and V. W. , The involvement of calcium in the protective and toxic (nonlinear) responses of rodent and human astroglial cells, Nonlinearity Biol Toxicol Med, vol.3, pp.79-95, 2005.

C. G. Schipke, I. Heuser, and O. Peters, Antidepressants act on glial cells: SSRIs and serotonin elicit astrocyte calcium signaling in the mouse prefrontal cortex, J Psychiatr Res, vol.45, pp.242-248, 2011.

K. Tang, T. Lu, C. Chang, Y. Lo, J. Cheng et al., Effect of fluoxetine on intracellular Ca2+levels in bladder female transitional carcinoma (BFTC) cells, Pharmacological Research, vol.43, pp.503-508, 2001.

B. Zhivotovsky and S. Orrenius, Calcium and cell death mechanisms: a perspective from the cell death community, Cell Calcium, vol.50, pp.211-221, 2011.

S. Orrenius, B. Zhivotovsky, and P. Nicotera, Regulation of cell death: the calcium-apoptosis link, Nat Rev Mol Cell Biol, vol.4, pp.552-565, 2003.

J. Mukherjee, M. K. Das, Y. Zy, and R. Lew, Evaluation of the binding of the radiolabeled antidepressant drug, 18F-fluoxetine in the rodent brain: an in vitro and in vivo study, Nucl Med Biol, vol.25, pp.605-610, 1998.

H. Mogami, L. Mills, C. Gallacher, and D. V. , Phospholipase C inhibitor, U73122, releases intracellular Ca2+, potentiates Ins(1,4,5)P3-mediated Ca2+ release and directly activates ion channels in mouse pancreatic acinar cells, Biochem J, vol.324, pp.645-651, 1997.

J. Ae and M. A. Van-waes, The Translocon: A Dynamic Gateway at the ER Membrane, Annual Review of Cell and Developmental Biology, vol.15, pp.799-842, 1999.

F. Van-coppenolle, V. Abeele, F. Slomianny, C. Flourakis, M. Hesketh et al., Ribosome-translocon complex mediates calcium leakage from endoplasmic reticulum stores, J Cell Sci, vol.117, pp.4135-4142, 2004.
URL : https://hal.archives-ouvertes.fr/inserm-00137717

M. C. Towler and D. G. Hardie, AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling, Circulation Research, vol.100, pp.328-341, 2007.

H. Imamura, K. P. Huynh-nhat, H. Togawa, K. Saito, R. Iino et al., Visualization of ATP levels inside single living cells with fluorescence resonance energy transfer-based genetically encoded indicators, Proceedings of the National Academy of Sciences of the United States of America, vol.106, pp.15651-15656, 2009.

M. E. Peter and P. H. Krammer, The CD95(APO-1/Fas) DISC and beyond, Cell Death Differ, vol.10, pp.26-35, 2003.

W. Dröge, Free Radicals in the Physiological Control of Cell Function, Physiological Reviews, vol.82, pp.47-95, 2002.

S. V. Lennon, M. Sj, and T. G. Cotter, Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli, Cell Prolif, vol.24, pp.203-214, 1991.

T. M. Caserta, A. N. Smith, A. D. Gultice, M. A. Reedy, and T. L. Brown, Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties, Apoptosis, vol.8, pp.345-352, 2003.

V. Gobin, D. Bock, M. Broeckx, B. Kiselinova, M. et al., Fluoxetine suppresses calcium Oncotarget 3196 www.impactjournals.com/oncotarget signaling in human T lymphocytes through depletion of intracellular calcium stores, Cell Calcium, vol.58, pp.254-263, 2015.

H. J. Kim, J. S. Choi, Y. M. Lee, E. Y. Shim, S. H. Hong et al., Fluoxetine inhibits ATP-induced [Ca(2+)](i) increase in PC12 cells by inhibiting both extracellular Ca(2+) influx and Ca(2+) release from intracellular stores, Neuropharmacology, vol.49, pp.265-274, 2005.

S. M. Cloonan and D. C. Williams, The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt's lymphoma, Int J Cancer, vol.128, pp.1712-1723, 2011.

M. Flourakis, F. Van-coppenolle, V. Lehen'kyi, B. Beck, R. Skryma et al., Passive calcium leak via translocon is a first step for iPLA2-pathway regulated store operated channels activation, FASEB J, vol.20, pp.1215-1217, 2006.
URL : https://hal.archives-ouvertes.fr/inserm-00137702

B. Landolfi, S. Curci, L. Debellis, T. Pozzan, and A. M. Hofer, Ca2+ homeostasis in the agonist-sensitive internal store: functional interactions between mitochondria and the ER measured In situ in intact cells, J Cell Biol, vol.142, pp.1235-1243, 1998.

U. De-marchi, C. , C. Demaurex, and N. , Uncoupling Protein 3 (UCP3) Modulates the Activity of Sarco/ Endoplasmic Reticulum Ca2+-ATPase (SERCA) by Decreasing Mitochondrial ATP Production, Journal of Biological Chemistry, vol.286, pp.32533-32541, 2011.

M. Hammadi, A. Oulidi, F. Gackière, M. Katsogiannou, C. Slomianny et al., Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78, The FASEB Journal, vol.27, pp.1600-1609, 2013.

N. K. Canová, E. Kmoní?ková, J. Martínek, Z. Zídek, and H. Farghali, Thapsigargin, a selective inhibitor of sarcoendoplasmic reticulum Ca2+-ATPases, modulates nitric oxide production and cell death of primary rat hepatocytes in culture, Cell Biol Toxicol, vol.23, pp.337-354, 2007.

K. Liu, Y. Lin, Y. Lin, J. Lee, Y. Wang et al., , 2015.

, Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

A. I. Tarasov, E. J. Griffiths, and G. A. Rutter, Regulation of ATP production by mitochondrial Ca2+, Cell Calcium, vol.52, pp.28-35, 2012.

R. Rizzuto, S. Marchi, M. Bonora, P. Aguiari, A. Bononi et al., 2+) transfer from the ER to mitochondria: when, how and why, Biochimica et biophysica acta, vol.1787, pp.1342-1351, 2009.

A. Spät, G. Szanda, G. Csordás, and G. Hajnóczky, Highand low-calcium-dependent mechanisms of mitochondrial calcium signalling, Cell Calcium, vol.44, pp.51-63, 2008.

M. Zoratti and I. Szabò, The mitochondrial permeability transition, Biochimica et Biophysica Acta (BBA) -Reviews on Biomembranes, vol.1241, pp.139-176, 1995.

M. Leist, B. Single, A. F. Castoldi, S. Kühnle, and P. Nicotera, Intracellular Adenosine Triphosphate (ATP) Concentration: A Switch in the Decision Between Apoptosis and Necrosis, The Journal of Experimental Medicine, vol.185, pp.1481-1486, 1997.

A. Rasola and P. Bernardi, Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis, Cell Calcium, vol.50, pp.222-233, 2011.

A. Rasola, M. Sciacovelli, B. Pantic, and P. Bernardi, Signal Transduction to the Permeability Transition Pore, FEBS letters, vol.584, pp.1989-1996, 2010.

P. Bernardi and A. Rasola, Calcium and cell death: the mitochondrial connection, Subcell Biochem, vol.45, pp.481-506, 2007.

D. Mekahli, G. Bultynck, J. B. Parys, D. Smedt, H. Missiaen et al., Endoplasmic-Reticulum Calcium Depletion and Disease. Cold Spring Harbor Perspectives in Biology, vol.3, p.4317, 2011.

S. M. Wille, S. G. Cooreman, H. M. Neels, and W. E. Lambert, Relevant issues in the monitoring and the toxicology of antidepressants, Crit Rev Clin Lab Sci, vol.45, pp.25-89, 2008.

S. H. Preskorn, Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Professional Communications, 1996.

D. J. Borys, S. C. Setzer, L. J. Ling, J. J. Reisdorf, L. C. Day et al., Acute fluoxetine overdose: a report of 234 cases, Am J Emerg Med, vol.10, pp.115-120, 1992.

S. Tauzin, B. Chaigne-delalande, E. Selva, N. Khadra, S. Daburon et al., The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway, PLoS Biol, vol.9, p.1001090, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00681970

B. Sorin, O. Goupille, A. M. Vacher, J. Paly, J. Djiane et al., Distinct cytoplasmic regions of the prolactin receptor are required for prolactin-induced calcium entry, J Biol Chem, vol.273, pp.28461-28469, 1998.

C. Vorndran, M. A. Poenie, and M. , New fluorescent calcium indicators designed for cytosolic retention or measuring calcium near membranes, Biophys J, vol.69, pp.2112-2124, 1995.

T. P. Stauffer, A. S. Meyer, and T. , Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells, Curr Biol, vol.8, pp.343-346, 1998.

A. Reagents, 000) was purchased from Thermo Fisher Scientific. Antibody against PDI (ADI-SPA-890, dilution 1:1,000) was obtained from Enzo Life Sciences. The secondary antibodies anti-mouse (#7076, dilution 1:1,000) and anti-rabbit (#7074, dilution 1:1,000) were obtained from Cell Signaling Technology, phospho-S6K(T389) (#9205, dilution 1:1,000), 4EBP1 (#9452, dilution 1:1,000), phospho-4EBP1(T37/46) (#2855, dilution 1:1,000), AKT (#4691, dilution 1:1,000), phospho-AKT(Ser473) (#4060, dilution 1:1,000), p62 (#5114, dilution 1:1,000), LC3 AB (#12741, dilution 1:1,000), b-actin (#4967, dilution 1:1,000), RAPTOR (#2280, dilution 1:1,000), p.6

, HA-p62 plasmid was a gift from Qing Zhong (Addgene plasmid #28027)

, Except for JURKAT (RPMI GIBCO), all the cells lines were grown in DMEM high glucose (4.5 g l À 1 ) (GIBCO) supplemented with 10% of fetal bovine serum (Dominique Dutscher), glutamine (2 mM), penicillin (Sigma, 100 U ml À 1 ) and streptomycin (Sigma, 100 mg ml À 1 ), at 37°C, 5% CO 2 in humidified atmosphere. Mycoplasma contamination check was carried out using the VenorGeM Kit, Cell culture. U2OS, HEK293A, A549 and JURKAT cells were obtained from ATTC. WT and ATG5 À / À MEFs were kindly provided by Patricia Boya

, The activation of glutaminolysis was performed by adding glutamine (2 mM final concentration) and leucine (0.8 mM final concentration). When indicated, DMKG was added to a final concentration of 0.2-2 mM. The different inhibitors were used concomitantly with the activation of glutaminolysis as follows: DON (40 mM), BPTES (30 mM)

S. Plasmids and . Transfections, The plasmid transfections were carried out using Jetpei (Polyplus Transfection) according to the manufacturer's instructions. Briefly, 70% confluent cells were transfected with 2-3 mg of plasmid. Twenty-four hours later cells were starved in the presence or absence of LQ for 48 h more. siRNA transfections were performed using Interferin@ (Polyplus Transfection) according to the manufacturer's instructions: cells at 50% of confluence were transfected with siRNA (final concentration 10 nM) in complete medium for 48 h and then starved with different treatments for another 72 h. All siRNAs were obtained from Dharmacon (on-target plus smartpool siRNA)





. Raptor,



;. Rictor and . Gcacuucgauua,




, After the respective treatments cells were washed two times with phosphate-buffered saline (PBS) and lysed with RIPA buffer containing a cocktail of protease inhibitor (P8340 Sigma), inhibitors of phosphatases (P0044 and P5726 Sigma) and PMSF 1 mM. Protein quantification was performed using BCA kit (Pierce), Immunoblots. 5 Â 10 6 JURKAT cells or 2 Â 10 6 U2OS, A549, HEK293 cells were seeded in 10 cm plates

, After two washes with cold PBS, cells were lysed with lP lysis buffer (40 mM Hepes pH 7.5, 120 mM NaCl, 1 mM EDTA, 0.3% CHAPS, protease inhibitor cocktail P8340 Sigma and 1 mM PMSF). Protein extracts were incubated overnight at 4°C with anti-HA magnetic beads, Thereafter beads were washed twice with cold PBS and eluted with Laemmli buffer for immunoblot analysis

, HEK293A, JURKAT) and the number of viable cells was determined after 24-144 h, using the TC20 Automated Cell Counter (Bio-Rad) according to the manufacturer's protocol. Briefly, after the respective treatments cells were detached with trypsin/EDTA and 10 ml of the cells suspension were mixed with 10 ml trypan blue 5% solution (Bio-Rad) and analysed with the TC20 cell counter (Bio-rad). To estimate the percentage of cell death, Cell proliferation and cell viability. 1.2 Â 10 5 cells were seeded for all the cell lines (U2OS, A549

. Real-time-pcr, The mRNAs from cells were isolated using Trisol (Invitrogen)

, One microgram of total mRNA was reverse transcribed using GoScript Reverse Transcription System (Promega), Specific primers for BAX

, Subcellular fractionation. 25 Â 10 6 cells were seeded in two 25 cm plates for each condition and after the respective treatment the cells were subjected to a subcellular fractionation using the Cell Fractionation Kit (#9038) of Cell Signaling Technology, following the manufacturer's recommendations. Flow cytometry. After treatment, cells were stained with annexin V and propidium iodide (PI) (Annexin V-early apoptosis detection kit, #6592 Cell Signaling Technology) following the manufacturer's instructions. Then, cells were analysed using BDFACS Canto BD-Biosciences flow cytometer

, For the co-localization experiments, after the fixation, cells were permeabilized using Triton-X 0.05% during 10 min, and then blocked with BSA 5% in PBS for 30 min. Finally, cells were incubated with the primary antibodies for 1 h at 37°C. After three washes with PBS, the cover slide was incubated for 1 h at 37°C with the appropriate secondary antibody (anti-rabbit Alexa488, dilution 1:400 or anti-mouse Alexa555, Confocal microscopy. 1.2 Â 10 5 cells were grown in coverslips with the respective treatments for 72 h

, À 1 ) with or without leucine/glutamine or DMKG during 72 h for U2OS and A549, and during 144 h for HEK293A. Similarly, U2OS cells were starved for amino acids, treated with LQ, RAP (100 nM) and/or 3MA (5 mM) as indicated for 72 h. After the treatment, 1.5 Â 10 3 cells (U2OS, A549) or 3 Â 10 4 (HEK293A) were seeded in a 3 cm plate containing complete media. After 14 days cells were fixed with paraformaldehyde 4% in PBS (30 min) and stained with violet crystal 5% for 15 min, Then, the plates were washed with water and imaged using ChemiDoc MP Imager

, Dehydration was performed with ethanol (50%, 70%, 95% and absolute ethanol). Thereafter, the samples were embedded in Epon/Ethanol and evaporated overnight at room temperature. The samples were processed for ultra-microtomy according to standard procedures. Finally sample imaging was performed using a Hitachi H7650 microscope operated at À 80 KV with a camera Gatan-11 MPx, After the respective treatment, cells were fixed for 1 h at 4°C in 4% paraformaldehyde in PBS, washed and fixed again 1 h at room temperature in aqueous 2% osmium tetroxide in 0.2 M sodium cacodylate

L. Bar-peled and D. M. Sabatini, Regulation of mTORC1 by amino acids, Trends Cell Biol, vol.24, pp.1-7, 2014.

D. Liko and M. N. Hall, mTOR in health and in sickness, J. Mol. Med. (Berl), vol.93, pp.1061-1073, 2015.

J. J. Howell, S. J. Ricoult, I. Ben-sahra, and B. D. Manning, A growing role for mTOR in promoting anabolic metabolism, Biochem. Soc. Trans, vol.41, pp.906-912, 2013.

A. Efeyan and D. M. Sabatini, mTOR and cancer: many loops in one pathway, Curr. Opin. Cell Biol, vol.22, pp.169-176, 2010.

S. Y. Sun, mTOR kinase inhibitors as potential cancer therapeutic drugs, Cancer Lett, vol.340, pp.1-8, 2013.

F. Chiarini, C. Evangelisti, J. A. Mccubrey, and A. M. Martelli, Current treatment strategies for inhibiting mTOR in cancer, Trends Pharmacol. Sci, vol.36, pp.124-135, 2015.

R. J. Deberardinis and T. Cheng, Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer, Oncogene, vol.29, pp.313-324, 2010.

V. H. Villar, F. Merhi, M. Djavaheri-mergny, and R. V. Durán, Glutaminolysis and autophagy in cancer, Autophagy, vol.11, pp.1198-1208, 2015.

W. W. Souba, Glutamine and cancer, Ann. Surg, vol.218, pp.715-728, 1993.

Z. Kovacevic and H. P. Morris, The role of glutamine in the oxidative metabolism of malignant cells, Cancer Res, vol.32, pp.326-333, 1972.

J. M. Matés, C. Pérez-gómez, I. Núñez-de-castro, M. Asenjo, and J. Márquez, Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death, Int. J. Biochem. Cell Biol, vol.34, pp.439-458, 2002.

E. A. Newsholme, B. Crabtree, and M. S. Ardawi, The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells, Biosci. Rep, vol.5, pp.393-400, 1985.

M. Li, C. Li, A. Allen, C. A. Stanley, and T. J. Smith, Glutamate dehydrogenase: structure, allosteric regulation, and role in insulin homeostasis, Neurochem. Res, vol.39, pp.433-445, 2014.

R. V. Durán, Glutaminolysis activates Rag-mTORC1 signaling, Mol. Cell, vol.47, pp.349-358, 2012.

R. C. Russell, H. X. Yuan, and K. L. Guan, Autophagy regulation by nutrient signaling, Cell Res, vol.24, pp.42-57, 2014.

X. Jiang, M. Overholtzer, and C. B. Thompson, Autophagy in cellular metabolism and cancer, J. Clin. Invest, vol.125, pp.47-54, 2015.

G. Kroemer, G. Mariño, and B. Levine, Autophagy and the integrated stress response, Mol. Cell, vol.40, pp.280-293, 2010.

A. J. Meijer, S. S. Lorin, E. F. Blommaart, and P. Codogno, Regulation of autophagy by amino acids and MTOR-dependent signal transduction, Amino Acids, vol.47, pp.2037-2063, 2014.

S. Fulda and K. Debatin, Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy, Oncogene, vol.25, pp.4798-4811, 2006.

M. Selvakumaran, Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways, Oncogene, vol.9, pp.1791-1798, 1994.

D. R. Alessi, Mechanism of activation of protein kinase B by insulin and IGF-1, EMBO J, vol.15, pp.6541-6551, 1996.

Y. Sancak, Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids, Cell, vol.141, pp.290-303, 2010.

D. C. Fingar, S. Salama, C. Tsou, E. Harlow, and J. Blenis, Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E, Genes Dev, vol.16, pp.1472-1487, 2002.

R. M. Young, Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress, Genes Dev, vol.27, pp.1115-1131, 2013.

A. Y. Choo, Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply, Mol. Cell, vol.38, pp.487-499, 2010.

S. Ng, Y. Wu, B. Chen, J. Zhou, and H. Shen, Impaired autophagy due to constitutive mTOR activation sensitizes TSC2-null cells to cell death under stress, Autophagy, vol.7, pp.1173-1186, 2011.

K. Hara, Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action, Cell, vol.110, pp.177-189, 2002.

D. H. Kim, mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery, Cell, vol.110, pp.163-175, 2002.

E. Chevet, C. Hetz, and A. Samali, Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis, Cancer Discov, vol.5, pp.586-597, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01152845

K. Kokame, K. L. Agarwal, H. Kato, and T. Miyata, Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress, J. Biol. Chem, vol.275, pp.32846-32853, 2000.

G. Mariño, M. Niso-santano, E. H. Baehrecke, and G. Kroemer, Selfconsumption: the interplay of autophagy and apoptosis, Nat. Rev. Mol. Cell Biol, vol.15, pp.81-94, 2014.

T. Noda, Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast, J. Biol. Chem, vol.273, pp.3963-3966, 1998.

G. E. Mortimore and C. M. Schworer, Induction of autophagy by amino-acid deprivation in perfused rat liver, Nature, vol.270, pp.174-176, 1977.

J. B. Li and L. S. Jefferson, Influence of amino acid availability on protein turnover in perfused skeletal muscle, BBA-Gen. Subj, vol.544, pp.351-359, 1978.

P. O. Seglen, B. Grinde, and A. E. Solheim, Inhibition of the lysosomal pathway of protein degradation in isolated rat hepatocytes by ammonia, methylamine, chloroquine and leupeptin, Eur. J. Biochem, vol.95, pp.215-225, 1979.

E. F. Blommaart, J. J. Luiken, P. J. Blommaart, G. M. Van-woerkom, and A. J. Meijer, Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes, J. Biol. Chem, vol.270, pp.2320-2326, 1995.

D. J. Klionsky, Guidelines for the use and interpretation of assays for monitoring autophagy, Autophagy, vol.12, pp.1-222, 2016.
URL : https://hal.archives-ouvertes.fr/hal-00214269

Y. Zhang, J. Gong, T. Xing, S. Zheng, and W. Ding, Autophagy protein p62/SQSTM1 is involved in HAMLET-induced cell death by modulating apotosis in U87MG cells, Cell Death Dis, vol.4, p.550, 2013.

M. M. Young, Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis, J. Biol. Chem, vol.287, pp.12455-12468, 2012.

E. Kim, Activation of caspase-8 contributes to 3,3-Diindolylmethaneinduced apoptosis in colon cancer cells, J. Nutr, vol.137, pp.31-36, 2007.

Z. Jin, Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling, Cell, vol.137, pp.721-735, 2009.

G. Bjørkøy, p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death, J. Cell Biol, vol.171, pp.603-614, 2005.

A. Duran, p62 is a key regulator of nutrient sensing in the mTORC1 pathway, Mol. Cell, vol.44, pp.134-146, 2011.

D. A. Tennant, Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death, Oncogene, vol.28, pp.4009-4021, 2009.

D. A. Tennant and E. Gottlieb, HIF prolyl hydroxylase-3 mediates alphaketoglutarate-induced apoptosis and tumor suppression, J. Mol. Med. (Berl), vol.88, pp.839-849, 2010.

M. Gao, P. Monian, N. Quadri, R. Ramasamy, and X. Jiang, Glutaminolysis and transferrin regulate ferroptosis, Mol. Cell, vol.59, pp.298-308, 2015.

K. E. O'reilly, mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt, Cancer Res, vol.66, pp.1500-1508, 2006.

A. Carracedo, Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer, J. Clin. Invest, vol.118, pp.3065-3074, 2008.

S. Chandarlapaty, AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity, Cancer Cell, vol.19, pp.58-71, 2011.

J. Tabernero, Dose-and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors, J. Clin. Oncol, vol.26, pp.1603-1610, 2008.

J. F. Linares, Amino acid activation of mTORC1 by a PB1-domain-driven kinase complex cascade, Cell Rep, vol.12, pp.1339-1352, 2015.

D. Medvetz, C. Priolo, and E. P. Henske, Therapeutic targeting of cellular metabolism in cells with hyperactive mTORC1: a paradigm shift, Mol. Cancer Res, vol.13, pp.3-8, 2015.

K. Chi, Addition of rapamycin and hydroxychloroquine to metronomic chemotherapy as a second line treatment results in high salvage rates for refractory metastatic solid tumors: a pilot safety and effectiveness analysis in a small patient cohort, Oncotarget, vol.6, pp.16735-16745, 2015.

R. Rangwala, Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma, Autophagy, vol.10, pp.1391-1402, 2014.

I. Mikaelian, Genetic and pharmacologic inhibition of mTORC1 promotes EMT by a TGF-b-independent mechanism, Cancer Res, vol.73, pp.6621-6631, 2013.

W. Palm, The utilization of extracellular proteins as nutrients is suppressed by mTORC1, Cell, vol.162, pp.259-270, 2015.