The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role

Abstract

Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central effects, orexins also play a role in various peripheral organs such as the intestine, pancreas, adrenal glands, kidney, adipose tissue and reproductive tract.In the past few years, an unexpected anti-tumoral role of orexins mediated by a new signaling pathway involving the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in both orexin receptors subtypes, the recruitment of the phosphotyrosine phosphatase SHP2 and the induction of mitochondrial apoptosis has been elucidated. In the present review, we will discuss the anti-tumoral effect of orexin/OXR system in colon, pancreas, prostate and other cancers, and its interest as a possible therapeutic target.

Orexin-A protects against oxygen-glucose deprivation/reoxygenation-induced cell damage by inhibiting endoplasmic reticulum stress-mediated apoptosis via the Gi and PI3K signaling pathways

“…Studies have shown that the Gi pathway [22,23] and Gq pathway [24][25][26] are involved in the action of OXA, and other signaling pathways such as cAMP, MAPK-ERK 1/2 , PI3K/Akt, and JNK are also involved [25]. Further studies have confirmed that OXA plays a protective role in diseases and pathophysiological processes through…”

Orexins as Novel Therapeutic Targets in Inflammatory and Neurodegenerative Diseases

“…In 2011, our group had demonstrated that OX1R but not OX2R was highly expressed in colon cancer cell lines and colorectal tumors from patients (139). It should be noted that: (1) no detection of prepro-orexin was observed in normal and tumoral colonic epithelia (139) and (2) OX1R was not detected in normal colon epithelium (22). Orexins treatment of digestive cancer cell lines derived from colon, pancreas and liver cancers (22, 139, 143) induced a strong cell death by apoptosis.…”

“…It should be noted that: (1) no detection of prepro-orexin was observed in normal and tumoral colonic epithelia (139) and (2) OX1R was not detected in normal colon epithelium (22). Orexins treatment of digestive cancer cell lines derived from colon, pancreas and liver cancers (22, 139, 143) induced a strong cell death by apoptosis. The orexin-induced apoptosis was mediated by the phosphorylation of two tyrosine-based motifs (ITIM) present in the receptor sequence.…”

“…In that respect, the crosstalk between the actors of inflammation and GPCRs has led to consider these receptors as very promising targets with potential therapeutic applications in inflammatory pathologies. Among the 800 members of the GPCR family, orexin receptors represent an archetype of a putative target for the treatment of chronic inflammatory diseases (22).…”

“…Although the precise source of orexins in disease conditions remains to be elucidated, the abnormal expression of orexin receptors in certain human pathologies has been demonstrated and may lead to new therapeutic targets. In this sense, the ectopic expression of OX1R in human IBD and digestive cancers has been shown, and the administration of exogenous OXA led to a protective effect of orexins in animal models of these pathologies (22).…”