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Rôle antitumoral de l'orexine A et des ligands biaisés dans les cancers digestifs : Impact sur le trafic intracellulaire d'OX1R

Abstract : Orexins are hypothalamic neuropeptides, which have two isoforms, A and B (OxA and OxB, respectively). They interact with two G protein-coupled receptor (GPCR) subtypes, OX1R and OX2R. Once activated, these two receptors induce the mobilization of intracellular Ca2+ via the Gq protein. In the team, where I began my PhD, it was clearly show that the orexins/OX1R system had anti-tumor properties in some cancers including colon cancer (Voisin et al., 2011). It has been showed that OxA but also OxB induce mitochondrial apoptosis via OX1R. These results mean that the orexins/OX1R system represents a potential target in the treatment of colon cancer.My first objective was to study the role of orexins and in particular OxA on pancreatic ductal adenocarcinoma (PDAC) in human. This work showed that OX1R was expressed in 96% of PDACs tested. In addition, I have shown that OX1R is expressed early in pre-cancerous lesions (PanIN). I have demonstrated that the PDAC-derived human cell line, the AsPC-1 line, expressed OX1R, and that OxA was able to induce mitochondrial apoptosis comparable to that observed in colon cancers (Voisin et al. 2011). Finally, suprisingly, my results show that almorexant, a DORA antagonist, has antitumor properties identical to OxA, the natural agonist of OX1R. The unexpected results of the almorexant with regard to its anti-tumor properties challenged me and thus determined the axis of my second objective. So I wanted to know if this effect was only related to the PDAC or if it was more widely effective in other cancers in particular colon cancer. For this, I studied the effect of almorexant in cell lines derived from human colon adenocarcinoma, lines HT-29 and LoVo. In addition, in collaboration with B. Robert's group (CRCM, INSERM U1194, Montpellier)we have developed, by a "phage display" strategy, an agonist antibody that mimicked the effects of OxA on the same cancer cells. My third objective was to study the phenomena of OX1R internalization under the action of OxA and its intracellular traffick by confocal microscopy and images analysis approaches. Indeed, so far, little or nothing is known. Several vesicle markers associated with the internalization of proteins have been used. Of course, in view of the almorexant unexpected effects, it seemed important for me to study its impact on the regulation.To conclude, the OX1 receptor is a potential target for the therapeutic treatment of human adenocarcinoma of the colon and pancreas. In addition, the demonstration that almorexant and the C2 antibody mimic the proapoptotic and antitumor effects of OxA, represents a very good alternative to the natural peptide whose disadvantages in terms of stability and administration may represent a brake in its possible therapeutic use. In addition, the membrane expression of the OX1 receptor within the cell and its fate is different depending on the ligand. These data are therefore of interest for a therapeutic point of view because the almorexant as the antibody C2 allow the OX1 receptor to stay expressed on the cell surface and thus to be available for its proapoptotic activity.
Keywords : OX1R Almorexant
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Submitted on : Monday, June 29, 2020 - 11:08:09 AM
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Stéphanie Dayot. Rôle antitumoral de l'orexine A et des ligands biaisés dans les cancers digestifs : Impact sur le trafic intracellulaire d'OX1R. Biologie cellulaire. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCC301⟩. ⟨tel-02883523⟩



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