molecules Review Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target Couvineau Alain * , Nicole Pascal, Gratio Valérie and Voisin Thierry INSERM UMR1149/Inflammation Research Center (CRI), Team “From Inflammation to Cancer in Digestive Diseases” Labeled by “la Ligue Nationale Contre le Cancer”, University of Paris, DHU UNITY, 75018 Paris, France; [email protected] (N.P.); [email protected] (G.V.); [email protected] (V.T.) * Correspondence: [email protected] 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. Keywords: orexins; neuropeptide; GPCR; apoptosis; cancer; gastroenterology Citation: Alain, C.; Pascal, N.; Valérie, G.; Thierry, V. Orexins/ Hypocretins and Cancer: A Neuropeptide as Emerging Target. 1. Introduction Molecules 2021, 26, 4849. https:// The identification of orexin, also termed hypocretin, is still young in science history [1]. doi.org/10.3390/molecules26164849 It was in the late 1990s, when two independent groups identified and characterized these neuropeptides in mouse hypothalamus [2,3]. Orexins (for more clarity in this text, the Academic Editor: Katalin single term “orexin” will be retained) were encoded by the same gene (hcrt) constituted Prokai-Tatrai of two exons producing a unique precursor named prepro-orexin which provided two peptide isoforms, orexin-A (OxA also termed hypocretin-1) and orexin-B (OxB also termed Received: 2 July 2021 hypocretin-2) [4]. The major role of orexins in the central nervous system (CNS) is to Accepted: 6 August 2021 Published: 11 August 2021 regulate wakefulness [5]. The dysregulation of orexin production in hypothalamus as well as the loss of orexins neurons leads to narcolepsy associated with cataplexy designated as Publisher’s Note: MDPI stays neutral narcolepsy type I [5]. [In addition to sleep regulation, orexins control energy homeostasis, with regard to jurisdictional claims in reward seeking, food consumption, drug addiction and motivation [6,7]. Although the published maps and institutional affil- central action of orexins has been widely described, some studies have demonstrated that iations. orexins also play a physiological role in the peripheral nervous system (6). Orexins are able to regulate reproductive and neuroendocrine functions, gastrointestinal motility, blood pressure, metabolism and energy balance. However, 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 Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. two orexin receptor subtypes that have been identified as orexin receptor type 1 (OX1R) This article is an open access article and orexin receptor type 2 (OX2R). These two receptors are associated with Gq protein distributed under the terms and and belong to the G protein-coupled receptor (GPCR) family [8]. The activation of these 2+ conditions of the Creative Commons receptors by orexins leads to the production of intracellular Ca , involving the activation Attribution (CC BY) license (https:// of αq, the phospholipase C and inositol triphosphate (IP3) production (Figure1)[8]. creativecommons.org/licenses/by/ Since the 2000s, it has been shown, in pathological conditions, that OX1R (but not 4.0/). OX2R) is abnormally expressed in peripheral cancers [9]. This ectopic expression of OX1R Molecules 2021, 26, 4849. https://doi.org/10.3390/molecules26164849 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 4849 2 of 10 has been observed in inflammation states, including intestinal bowel diseases (IBD), multi- ple sclerosis, pancreatitis and also 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 2 of 11 demonstrating its putative therapeutic interest in treatment of these pathologies, in par- ticular, in cancer [6,13]. A recent report focused on the connection between narcolepsy, Alzheimer’s and Parkinson’s diseases—where a dysregulation of orexin signaling was observed—andactivation of these cancer, receptors suggesting by orexins that the leads modulation to the production of orexin signalingof intracellular could Ca have2+, in- a putativevolving therapeuticthe activation role of in α cancerq, the phospholipase treatment [14]. C In and this inositol respect, triphosphate the present review (IP3) produc- reports thetion anti-tumoral (Figure 1) [8]. role of the orexins/OX1R system in various cancers. Figure 1. Structure of orexins and their receptors and main signaling pathways activated by orexins in cancer cells. DsB, disulfide bridge; IP3, inositol tri-phosphate; PLC, phospholipase; SHP2, Src ho- Figure 1. Structure of orexins and their receptors and main signaling pathways activated by orexins mologyin cancer 2 (SH2) cells. domainsDsB, disulfide of SH2-containing bridge; IP3, phosphatase inositol tri-phosphate; 2; cAMP, cyclic PLC, adenosine phospholipase; monophosphate; SHP2, Src Akt,homology protein 2 kinase (SH2) B;domains JNKs, c-jun of SH2-containing N-terminal kinases; phosphatase ERK1/2, 2; extracellular cAMP, cyclic signal-regulated adenosine monophos- kinase 1phate; and 2; Akt, ITIM, protein immunoreceptor kinase B; JNKs, tyrosine-based c-jun N-terminal motifs; kinases; Src, Src ERK1/2, kinases. extracellular signal-regulated kinase 1 and 2; ITIM, immunoreceptor tyrosine-based motifs; Src, Src kinases. 2. Orexins and Orexin Receptors OrexinsSince the (OxA 2000s, and it OxB)has been are encodedshown, in by pa thethological same mRNA conditions, which that produced OX1R (but a com- not monOX2R) precursor is abnormally [2]. OxA expressed is a peptide in peripheral of 33 amino cancers acids [9]. that This has ectopic a pyroglutamyl expression residueof OX1R inhas the been N-terminal observed position, in inflammation two disulfide states, bridges including between intestinal C6–C12 bowel and diseases C7–C14, (IBD), and mul- an amidatedtiple sclerosis, C-terminal pancreatitis end (Figure and also1)[ in15 digest]. OxBive iscancers a peptide such of as 28 colon, amino pancreas acids that and alsoliver hascancers a C-terminal [4,10,11] endand amidatednon-digestive (Figure cancers1)[ 3 such]. These as prostate two peptides cancer are[12]. highly The activation conserved of inthis all ectopically mammalians expressed [15]. It should OX1R be induces noted thatanti-inflammatory orexin-like genes and are anti-tumoral not found in effects, inver- α tebratesdemonstrating [15]. Solution its putative structures therapeutic of OxA interest and OxB in treatment reveal the of presence these pathologies, of two -helices in par- betweenticular, in residues cancer S13-G22 [6,13]. A and recent G24-T32 report for focused OxA and on residues the connection G6-S18 and between H21-T27 narcolepsy, for OxB α (FigureAlzheimer’s1). These and twoParkinson’s-helice diseases—where domains are linked a dysregulation by a small flexible of orexin domain signaling(Figure was 1ob-) . Structure–function relationship analyses of OxB revealed that the C-terminal domain N20- served—and cancer, suggesting that the modulation of orexin signaling could have a pu- M28 is crucial for the peptide activity [16]. However, the N-terminal moiety of OxB from tative therapeutic role in cancer treatment [14]. In this respect, the present review reports residue R1 to G6 is not essential for its activity [16]. As mentioned in the introduction, these the anti-tumoral role of the orexins/OX1R system in various cancers. two peptides are able to interact with two receptor subtypes, OX1R and OX2R. OX1R had a better affinity for OxA than OxB, whereas OX2R had the same affinity for two peptides [8]. 2. Orexins and Orexin Receptors Associated with the strong impact of orexins on sleep regulation, inhibition of orexin receptorsOrexins represents (OxA and an important OxB) are encoded therapeutic by optionthe same to mRNA treat insomnia which produced [17]. In this a common context, pharmaceuticalprecursor [2]. OxA industries, is a peptide but also of academic33 amino laboratories,acids that has have a pyroglutamyl developed various residue antago- in the nistsN-terminal that are position, able to regulate two disulfide wake–sleep bridges cycles between [18]. C6–C12 Many molecules and C7–C14, have and been an produced amidated C-terminal end (Figure 1) [15]. OxB is a peptide of 28 amino acids that also has a C-termi-