# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 3 Orexins and Cancer
### Circadian Rhythm and Cancer
\begin{table}
\begin{tabular}{c c c} \hline
**Tumor** & **Orexigenic System** & **References** \\ \hline Acute lymphoblastic leukemia & Plasma orexin levels increased in patients receiving chemoradiotherapy. & [84, 85] \\  & Dexamethasone chemotherapy did not block the orexinergic signaling. & \\ \hline  & Prepro-orexin mRNA, orexin A (not orexin B) and OXR1/OXR2 upregulation. & \\  & Orexin A, but not orexin B, augmented normal/adrenocortical adenoma & \\  & cell proliferation. & \\  & NCI-H295R cell line: orexin A decreased OXR2 expression and increased OXR1 & \\  & expression, cell proliferation, and cortisol release. & [80, 81, 86, 87, 88, 89] \\  & Pheochromocytoma: OXR1 expression but not OXR2. & \\  & Orexin A/B, via OXR2, favor catecholamine release from pheochromocytomas. & \\  & PC12 cells: no OXR1/OXR2 expression, but orexin A/B decreased the level of & \\  & tyrosine hydroxylase; effect exerted via non-orexin receptors. & \\ \hline Breast cancer & Orexinergic hypothalamic neurons involved in tumor-induced & [90] \\  & changes in metabolism. & \\ \hline Cervical cancer & OXR2 overexpression. & [91] \\ \hline  & OXR1 expression. & \\  & Orexins promoted apoptosis and decreased tumor volume. & \\  & Apoptosis observed in tumor cells resistant to chemotherapy drugs. & \\  & Orexin A promoted autophagy in cancer cells. & [60, 82, 93, 98, 99] \\  & High OXR1 expression in colon cancer cells and colonic epithelium of patients with & \\  & ulcerative colitis. & \\ \hline Endometial cancer & OXR2, frequently lacking, related to OXR2 hypermethylation. & [58] \\ \hline  & OXR1 expression. & \\  & Orexin A increased OXR1 expression, blocked apoptosis, and augmented viability & \\  & and cell proliferation. & \\ Gastric cancer & OXR1 overexpression, via MAPK-dependent caspases and src-tyrosine, promoted & [82, 101, 102, 103, 104] \\  & tumor regression in gastric adenocarcinoma. & \\  & Orexin A upregulation, OXR1/OXR2 expressions downregulated and & \\  & high inflammation. & \\ \hline Glioma & Orexin A, via a caspase-dependent mechanism, decreased tumor cell viability. & [105] \\  & C6 cells express OXR1/OXR2, which do not mediate cell proliferation. & [107] \\ \hline Head and neck cancer & Methylation status of the orexin precursor gene promoter related to cell survival and & [105] \\  & recurrence. An epigenetic marker for risk/prognosis. & \\ \hline  & OXR1 mRNA but not OXR2 mRNA expression. & \\  & OXR1 located in the nuclei of cancer cells. & \\  & Orexin A favored HIF-1a expression and its nuclear accumulation. & \\  & Orexin A increased glucose uptake and glucose transporter 1 expression in & \\  & tumor cells. & [108, 109, 111] \\  & Orexin A regulated cellular metabolism towards mitochondrial glucose oxidation & \\  & rather than glycolysis. & \\  & Stress and depression increased, via orexin downregulation, the risk of & \\  & tumor development. & \\ \hline  & Orexin A expression. & \\  & Orexin A/B promoted growth suppression and apoptotic mechanisms. & \\  & Orexin A exerted an anti-apoptotic and antioxidant actions and decreased & \\  & biochemical markers of cell death. & \\ Neuroblastoma & Orexin A decreased the levels of intracellular reactive oxygen species and & \\  & cytochrome c, Bax/Bcl-2 ration, and caspase 3 activity; HIF-1\(\alpha\) induction. & \\  & OXR1 regulated, via diacylglycerol-activated channels, the entry of calcium into & \\ \hline  & Orexin A, via OXR1, promoted tumor cell proliferation and protected these cells & \\  & from apoptosis. & \\  & OXR1 blockade promoted apoptosis. & \\  & Orexin A, via the SHP2 signaling cascade, promoted mitochondrial apoptosis in & \\  & AsPC-1 cells. & \\ Pancreatic cancer & Orexin A decreased tumor volume by apoptosis. & [19, 110, 120] \\  & Orexin A blocked tumor development in tumors chemoresistant to & \\  & abraxane or gemcitabine. & \\  & Orexins blocked tumor growth and promoted apoptosis in the AR42] pancreatic & \\  & acinar cell line expressing OXR2. & \\ \hline \end{tabular}
\end{table}