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Identification des mécanismes moléculaires impliqués dans la résistance des cellules à une carence en acides aminés.

Abstract : Tumor development can be characterized by the formation of hypoxic area deprived in nutrients. Due to their genetic instability, tumor cells can become resistant to this apoptotic condition. Among the resistance mechanisms, those involved in cell survival against amino acids restriction is poorly known. Amino acids deprivation is particularly deleterious as nine of them cannot be synthetized de novo. The aim of this work was to identify the mechanisms by which tumor cells can survive to long-term amino acids deprivation. For that purpose, we exerted a selective pressure on mouse embryonic fibroblast by exposing them to amino acids deprivation for several months. We generated clones able to survive and proliferate in deprived amino acids medium. Firstly, we characterized the capacity of proliferation and survival of several resistant clones in amino acid deprivation condition. Secondly, we studied several signaling pathways which are regulated during this condition. We have found that every clones present an alteration of the GCN2 pathway, and notably, a low expression of its major actor, the protein ATF4, when compared to the parental cells. We have shown with shRNA experiment that this underexpression promotes cell survival during amino acid deprivation. The association between decreased expression of ATF4 and better survival in amino acid deprivation condition was also found in a pancreatic cancer cell line, BxPC-3. ATF4 overexpression in this resistant cell line restores the apoptotic effect of ATF4 during amino acid deprivation. We have also studied how cells can provide themselves in amino acids from the extracellular environment. We have observed that one of the clone cell line presents a high level of macropinocytosis and that, the inhibition of this mechanism decreases its survival during amino acid deprivation. Thanks to our approach, we were able to highlight mechanisms which confers to cell resistance to amino acid deprivation. By observing those mechanisms in cancer cell lines, we confirmed the relevance of our approach to identify such mechanisms.
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https://tel.archives-ouvertes.fr/tel-01661418
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Submitted on : Monday, December 11, 2017 - 11:33:22 PM
Last modification on : Tuesday, March 17, 2020 - 1:48:45 AM

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2016CLF1MM26_MESCLON.pdf
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  • HAL Id : tel-01661418, version 1

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Florent Mesclon. Identification des mécanismes moléculaires impliqués dans la résistance des cellules à une carence en acides aminés.. Médecine humaine et pathologie. Université d'Auvergne - Clermont-Ferrand I, 2016. Français. ⟨NNT : 2016CLF1MM26⟩. ⟨tel-01661418⟩

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