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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the eleventh most frequent cancer in the United States, accounting for 53,070 new cases per year, and it will stand as the second cause of cancer related-death by 2030 [1,2,3,4]
We investigated the ability of orexin-A to promote apoptosis: 1) in vitro studies by using PDAC cell lines as AsPC-1 cells; 2) ex vivo studies by using tissue culture derived from patients
OX1R expression in PDAC was not correlated with patient age, gender, disease recurrence, disease-free survival, overall survival, tumor size, TNM stage, lymph node metastasis, or tumor differentiation (Table 1)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the eleventh most frequent cancer in the United States, accounting for 53,070 new cases per year, and it will stand as the second cause of cancer related-death by 2030 [1,2,3,4]. The low 5-year survival rate (about 7%) is due to highly invasive behavior with frequent non-resectability at initial diagnosis. This tumor is mainly drugresistant to classic chemotherapeutic agents because of the association of a fibrotic, immunosuppressive, and hypoxic microenvironment with numerous tumor mutations that activate proto-oncogene expression, block tumor suppressor genes or interfere with apoptosis [5]. G-protein coupled receptors (GPCRs) belong to a large superfamily of cell surface signaling proteins involved in many pathophysiological processes [6]. Diverse GPCRs are overexpressed in tumor cells, and are involved in the initiation and/or progression of cancer by stimulating or inhibiting proliferation and/or apoptosis [7]. We have recently demonstrated the aberrant expression of the orexin receptor sub-type 1, OX1R, in primary colorectal tumors, whereas no expression could be found in normal colon [8]
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