# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 3 Orexins and Cancer
### Pancreatic Cancer  
Orexin A, through OXR1, promotes the proliferation of pancreatic cancer PANC1 cells and protects these cells from apoptosis [119]. The peptide activates the Akt/mTOR signaling pathway, which favors cancer cell proliferation by blocking c-myc/caspase 9/Bcl-2-mediated apoptosis [119]. However, the blockade of OXR1 promoted apoptosis by regulating c-myc, caspase 9, and Bcl-2 levels in pancreatic cancer cells. Thus, OXR1 is a potential antitumor target.  
Pancreatic ductal adenocarcinoma (PDAC) expressed OXR1, but not OXR2, and this expression was independent of age, gender, and tumor grade; OXR1 was also observed in pancreatic intraepithelial neoplasia, a PDAC pre-neoplastic lesion [120]. Orexin A, through the SHP2 signaling cascade, promoted mitochondrial apoptosis in AsPC-1 cells (a PDAC cell line) and in PDAC cells isolated from cancer patients [120]. Orexin A also decreased tumor volume (due to apoptosis) in those animals xenografted with AsPC-1 or PDAC cells, but the peptide did not exert an antitumor action against HPAF-II cells in which OXR1 was absent [120]. PDAC often develops chemoresistance to treatments with abraxane (Nab-paclitaxel) or gemcitabine. Orexin A, through OXR1, promoted an antitumor action by activating mitochondrial pro-apoptotic processes [19]. This peptide blocked the growth of pancreatic cancer cells, inhibited tumor volume in preclinical experimental models, and its co-administration with abraxane or gemcitabine was additive regarding the blockade of cancer cells' growth and tumor development [19]. Orexin A promoted a strong blockade against tumor development in chemoresistant xenograft tumors with abraxane or gemcitabine and promoted the death of pancreatic cancer cells resistant to these compounds [19]. Moreover, ex vivo, in vivo, and in vitro studies have demonstrated that orexin A and almorexant (ACT-078573, a dual OXR1 and OXR2 antagonist) promoted apoptosis in PDAC cells via OXR1 [120]. Most PDAC tissues showed OXR1, but this was not observed in adjacent normal exocrine pancreas; OXR1 expression was also observed in pre-cancerous lesions and orexin A or almorexant promoted apoptosis in AsPC-1 cells expressing OXR1, which was inhibited with NSC-87877, a tyrosine phosphatase SHP2 inhibitor [120]. Compared to control samples, a higher number of cancer cells expressing caspase 3 was observed after treatment with orexin A, but cell proliferation was not changed and, in in vivo experiments, orexin A or almorexant significantly decreased tumor growth [120]. The data suggest the potential use of both orexin A and almorexant to treat PDAC. Finally, orexins promoted growth inhibition and apoptosis in the rat pancreatic acinar AR [119; 120] cell line, which expresses OXR2 but not OXR1, and in Chinese hamster ovary cells transfected with OXR2 cDNA [12].  
Orexin A, via OXR1, increased the release of insulin by rat insulinoma INS-1 cells by activating Akt and its downstream target mTOR [121]. These mechanisms were blocked with SB-674,042, a selective OXR1 antagonist, or with PF-04691502, a PI3k/mTOR antagonist. This study also showed that orexin A increased mTOR phosphorylation and OXR1 expression in insulinoma cells [121].