Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives

Abstract

Peptides promote the mitogenesis and migration of tumor cells, and cancer cells overexpress peptide receptors. The involvement of the orexinergic system in cancer is reviewed here, including thirteen cancer types (e.g., adrenocortical adenoma, breast, colon, gastric, liver, neuroblastoma, pancreas, prostate). An upregulation of the orexinergic system has been reported in many tumors, and orexin receptors (OXRs) mediate a dual effect: apoptosis in some tumors and a proliferative action in others. OXR antagonists or agonists are potential antitumor agents against tumors expressing OXRs. The complexities of the biological processes associated with the orexigenic system are also described in the review, as they may provide the basis for the development of new therapies: OXR dimerization/oligomerization, epigenetic mechanisms controlling the orexinergic system, possible biomarkers of this system for tumor risk/prognosis, protective effects mediated by orexins against chemotherapeutic drugs, the combination therapy of OXR antagonists/agonists with radiotherapy or chemotherapy, and the anti-inflammatory effects mediated by orexins. Taking these data into account, future therapeutic applications as well as research lines to be developed are also mentioned and discussed. This knowledge will allow for the development of antitumor strategies in the future.

Unraveling the function and structure impact of deleterious missense SNPs in the human OX1R receptor by computational analysis

“…Signaling through OX1R is well established for its role in neuronal depolarization, which enhances excitability and firing rates through the activation of a non-selective cation current. Moreover, the orexin/OX1R system has been linked to inducing mitochondrial apoptosis, leading to a substantial reduction in cell growth across various cancer lines 58 , 59 . An analysis of the structure positioning of the most detrimental mutant proteins on OX1R, in comparison with the µ-opioid protein complex as a GPCR receptor, revealed that the mutants R144C, I148N, and A297D are situated in regions directly interacting with the Gi protein 60 .…”

Orexins in apoptosis: a dual regulatory role

“…Due to these phosphorylation processes, it leads to the recruitment and activation of the phosphotyrosine phosphatase SHP-2 ( Voisin et al, 2008 ). Consequently, this activation initiates mitochondrial apoptosis mediated by cytochrome c ( Marcos and Coveñas, 2023 ).…”

Rethinking the Role of Orexin in the Regulation of REM Sleep and Appetite

“…Moreover, in many types of cancer, an upregulation of the orexinergic system has been reported [53] that seems to have a dual effect [69]. In fact, in some tumors apoptosis has been observed associated with orexin upregulation while, in others, a proliferative effect has been found.…”