Abstract
Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.
Highlights
Molecules 2021, 26, 4849. https://The identification of orexin, termed hypocretin, is still young in science history [1].It was in the late 1990s, when two independent groups identified and characterized these neuropeptides in mouse hypothalamus [2,3]
The dysregulation of orexin production in hypothalamus as well as the loss of orexins neurons leads to narcolepsy associated with cataplexy designated as narcolepsy type I [5]. [In addition to sleep regulation, orexins control energy homeostasis, reward seeking, food consumption, drug addiction and motivation [6,7]
In 2004, we demonstrated that OX1R was ectopically expressed in colon cancer and neuroblastoma in which the activation of these receptors by orexins induced an inhibition of cell growth [9]
Summary
The identification of orexin, termed hypocretin, is still young in science history [1]. Few reports have been dedicated to orexins’ role in the peripheral nervous system, indicating that these peripheral actions remain relatively controversial [6] Orexins mediate these biological actions by activating two orexin receptor subtypes that have been identified as orexin receptor type 1 (OX1R). Has been observed in inflammation states, including intestinal bowel diseases (IBD), multiple sclerosis, pancreatitis and in digestive cancers such as colon, pancreas and liver cancers [4,10,11] and non-digestive cancers such as prostate cancer [12] The activation of this ectopically expressed OX1R induces anti-inflammatory and anti-tumoral effects, Molecules 2021, 26, x FOR PEER REVIEW of 11 demonstrating its putative therapeutic interest in treatment of these pathologies, in 2particular, in cancer [6,13]. N-terminal kinases; ERK1/2,2;extracellular signal-regulated kinase homology (SH2) B; domains of SH2-containing phosphatase cAMP, cyclic adenosine monophos1phate; and 2;Akt, ITIM, immunoreceptor tyrosine-based motifs;kinases; Src, Src ERK1/2, kinases. extracellular signal-regulated protein kinase B; JNKs, c-jun N-terminal kinase 1 and 2; ITIM, immunoreceptor tyrosine-based motifs; Src, Src kinases
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