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In vitro, in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma

Stéphanie Dayot, Daniela Speisky, Anne Couvelard, Pierre Bourgoin, Valérie Gratio, Jérôme Cros, Vinciane Rebours, Alain Sauvanet, Pierre Bedossa, Valérie Paradis, Philippe Ruszniewski, Alain Couvineau and Thierry Voisin _

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Oncotarget. 2018; 9:6952-6967. https://doi.org/10.18632/oncotarget.24084

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Abstract

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

Correspondence to:

Thierry Voisin, email: thierry.voisin@inserm.fr

Alain Couvineau, email: alain.couvineau@inserm.fr

Keywords: pancreatic cancer; orexin receptor; GPCR; apoptosis; patient-derived xenograft

Received: July 29, 2017     Accepted: January 02, 2018     Published: January 09, 2018

ABSTRACT

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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