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, Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement, Psychopharmacology, vol.215, pp.191-203, 2011.
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, Orexin A modulates INS-1E cell proliferation and insulin secretion via extracellular signal-regulated kinase and transient receptor potential channels, Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society, vol.67, pp.643-652, 2016.
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, Lack of expression of preproorexin and orexin receptors genes in human normal and prostate cancer cell lines, Folia Histochemica Et Cytobiologica, vol.53, pp.333-341, 2015.
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, Orexin-A is composed of a highly conserved C-terminal and a specific, hydrophilic N-terminal region, revealing the structural basis of specific recognition by the orexin-1 receptor, Journal of Peptide Science, vol.12, pp.443-454, 2006.
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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
, Elles vont interagir avec deux sous-types de récepteurs couplés aux protéines G (RCPG), OX1R et OX2R. Une fois activés, ces deux récepteurs induisent la mobilisation du Ca 2+ intracellulaire via la protéine Gq. Au sein de l'équipe où j'ai effectué ma thèse, il a été clairement montré que le système orexines/OX1Ravait des propriétés anti-tumorales dans certains cancers, Par Stéphanie Dayot Les orexines sont des neuropeptides hypothalamiques qui possèdent deux isoformes, A et B (OxA et OxB, respectivement)
, Enfin contre toute attente, j'ai montré que l'almorexant, un antagoniste de type DORA (Dual Orexin Receptor Antagonist) avait des propriétés antitumorales identique à l'OxA, l'agoniste naturel d'OX1R. Les résultats inattendus de l'almorexant vis-à-vis de ses propriétés antitumorales m'ont interpellée et ont ainsi déterminé l'axe de mon deuxième objectif. J'ai donc voulu savoir si cet effet était uniquement lié au PDAC ou s'il était plus largement dans d'autres cancers. Pour cela j'ai étudié l'effet de l'almorexant dans des lignées cellulaires dérivées d'adénocarcinomes coliques humains, les lignées HT-29 et LoVo. De plus, en collaboration avec le groupe de B. Robert (CRCM, INSERM U1194, Montpellier) nous avons développé, par une stratégie de « phage display », un anticorps agonis te dont j'ai montré qu'il mimait les effets de l'OxA sur les mêmes lignées cellulaires. Mon troisième objectif a été 'étudier les phénomènes d'internalisation d'OX1R sous l'action d'OxA et son devenir intracellulaire par des approches de microscopie confocale et d'analyse d'images. En effet, à ce jour peu, pour ne pas dire rien n'est connu. Plusieurs marqueurs de vésicules associées à l'internalisation des protéines ont été utilisés. Bien entendu, à la vue des effets inattendus, de l'almorexant, il me paraissait important d'étudier son impact sur ces phénomènes de régulation. Pour conclure, le récepteur OX1 est une cible potentielle pour le traitement thérapeutique des adénocarcinomes humains du côlon et du pancréas. De plus, la mise en évidence que l'almorexant et l'anticorps C2 miment les effets proapoptotiques et antitumoraux de l'OxA, représente une très bonne alternative au peptide naturel dont les inconvénients en terme de stabilité et d'administration peuvent représenter un frein dans son utilisation thérapeutique éventuelle. De plus, l'expression membranaire du récepteur OX1 au sein de la cellule et son devenir sont différentes en fonction du ligand. Ces données ont donc un intérêt d'un point de vue thérapeutique car l'almorexant comme l'anticorps C2 permettent au récepteur OX1 de rester exprimé à la surface cellulaire et ainsi d'être disponible pour son activité proapoptotique. Orexins are hypothalamic neuropeptides, which have two isoforms, A and B (OxA and OxB, respectively), Il a été montré que l'OxA mais aussi l'OxB induisait une apoptose mitochondriale via OX1R. Ces résultats signifient que le système orexines/OX1R représente une cible potentielle dans le traitement du cancer du côlon. Mon premier objectif de thèse a été d'étudier le rôle des orexines et en particulier de l'OxA sur l'adénocarcinome canalaire du pancréas (PDAC) chez l'Homme. Ces travaux m'ont permis de montrer qu'OX1R était exprimé dans 96% des PDAC testés. De plus, j'ai montré qu'OX1R était exprimé précocement dans les lésions précancéreuses (PanIN). J'ai démontré que la lignée cellulaire humaine dérivée d'un PDAC, la lignée AsPC1-exprimait OX1R et que l'OxA était capable d'induire une apoptose mitochondriale comparable à celle observée dans les cancers du côlon, 2011.