In vitro, in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma
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Stéphanie Dayot1,*, Daniela Speisky1,*, Anne Couvelard1,2, Pierre Bourgoin1, Valérie Gratio1, Jérôme Cros1,4, Vinciane Rebours1,3, Alain Sauvanet1,3, Pierre Bedossa1,4, Valérie Paradis1,4, Philippe Ruszniewski1,3, Alain Couvineau1,# and Thierry Voisin1,#
1INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
2Département de Pathologie Beaujon-Bichat, AP-HP, Hôpital Bichat, Huchard, 75018 Paris, France
3Service de Pancréatologie-Gastroentérologie PMAD, Pôle des Maladies de l’Appareil Digestif, AP-HP, Hôpital Beaujon, 92118 Clichy, France
4Département de Pathologie Beaujon-Bichat, AP-HP, Hôpital Beaujon, 92118 Clichy, France
*These authors contributed equally to this work
#Shared last authors
Thierry Voisin, email: email@example.com
Alain Couvineau, email: firstname.lastname@example.org
Keywords: pancreatic cancer; orexin receptor; GPCR; apoptosis; patient-derived xenograft
Received: July 29, 2017 Accepted: January 02, 2018 Published: January 09, 2018
Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant in vitro and ex vivo. We analyzed in vivo the hypocretin-1/orexin-A and almorexant effect on tumor growth in mice xenografted with PDAC cell lines expressing, or not, OX1R. Ninety-six percent of PDAC expressed OX1R, while adjacent normal exocrine pancreas did not. OX1R was expressed in pre-cancerous lesions. In vitro, under hypocretin-1/orexin-A and almorexant, the OX1R-positive AsPC-1 cells underwent apoptosis, abolished by the tyrosine phosphatase SHP2 inhibitor, NSC-87877, whereas the OX1R-negative HPAF-II cell line did not. These effects were mediated by phosphorylation of OX1R and recruitment of SHP2. Ex vivo, caspase-3 positive tumor cells were significantly higher in fresh tumour slices treated 48h with hypocretin-1/orexin-A, as compared to control, whereas cellular proliferation, assessed by Ki-67 index, was not modified. In vivo, when AsPC-1 cells or patient-derived cells were xenografted in nude mice, hypocretin-1/orexin-A or almorexant, administrated both starting the day of cell line inoculation or after tumoral development, strongly slowed tumor growth. Hypocretin-1/orexin-A and almorexant induce, through OX1R, the inhibition of PDAC cellular growth by apoptosis. Hypocretins/orexins and almorexant might be powerful candidates for the treatment of PDAC.
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