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.