# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 3 Orexins and Cancer
### Colon Cancer
The C-terminus of orexin B favored the induction of OXR1-mediated apoptosis in colon tumor cells, and this means that orexin B interacted with some residues belonging to the OXR1 [23]. Thus, OXR1 residues (K (120, 321), P (123), Y (124), N (318), F (340), T(341), H (344), W (345)) are crucial for orexin B recognition and orexin B/OXR1-induced apoptosis; alanine substitution of orexin B residues (L (11, 15, 26), A (22), G (24), I (25), M (28)) altered the binding affinity of the peptide, and substitution of Q (16), A(17), S (18), N (20) and T (27) residues blocked apoptosis in OXR1 expressing cells [23]. This study shows the importance of knowing in-depth the structure-function relationships between orexins and their receptors for the developing of new antitumor compounds. It has been observed that orexin A inhibited exosomal PD-L1 expression in colon cancer and blocked the JAKZ/STAT3 signaling pathway promoting T cell activity [96]. Moreover,cholecystokinin A receptor and OXR1 heterodimerize in human HT-29 colon cancer and HEK293 cells; the stimulation of OXR1/cholecystokinin A receptor heterodimers with both orexin A and cholecystkinin decreased the migration and activation of G\(\alpha\)q/G\(\alpha\)i2/G\(\alpha\)12/G\(\alpha\)13 in HT-29 cells when compared to that observed after stimulation with orexin A or cholecyststokinin alone; however, the interaction of both receptors with \(\beta\)-arrestin was not altered [97]. This is important, since OXR1/cholecystokinin heterodimerization mediates antimigratory and antimetastatic effects. Orexin A, via the ERK signaling pathway, promoted autophagy in human HCT-116 colon cancer cells, inhibited the viability of these cells, and upregulated ERK phosphorylation; both apoptosis and autophagy (an accumulation of punctuate microtubule-associated protein-1 light chain 3 occurs) were activated by the peptide [98]. However, U0126 (an ERK inhibitor) or chloroquine (an autophagy inhibitor) decreased autophagy and blocked ERK phosphorylation in colon cancer cells [98]. Because autophagy can promote tumorigenesis by promoting tumor cell proliferation, the blockade of autophagy could be a useful antitumor strategy. Finally, ulcerative colitis, an inflammatory bowel disease, affects both colon and rectum mucosa and is a risk factor for colon cancer development [99]. A high OXR1 expression has been reported in colon cancer cells as well as in the colonic epithelium of most patients suffering from ulcerative colitis, but this was not observed in the normal mucosa [99]. The administration of orexin A exerted an anti-inflammatory effect in colitis experimental murine models, and this was due to a decrease in the level of pro-inflammatory cytokines in immune cells (e.g., T cells); moreover, orexin A blocked the release of cytokines (e.g., interleukins 1\(\alpha\), 1\(\beta\), 6, 8, and 17, tumor necrosis factor \(\alpha\)) and the canonical NF-\(\kappa\)B activation in immune cells [99]. The anti-inflammatory effect promoted by orexin A was also due to PLC activation, which promoted the release of intracellular calcium, and NF-\(\kappa\)B inactivation, which regulated the release of inflammatory cytokines [100]. Thus, orexin A could be a promising treatment against ulcerative colitis and other intestinal bowel diseases such as [PERSON]'s disease in which OXR1 is expressed [16] and, in addition to the anti-inflammatory effect mediated by orexin A, the peptide could also prevent the development of tumors by promoting apoptosis in tumor cells.