# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 1 Introduction
### Signaling Pathways  
The two major signal transduction pathways associated with ligand-receptor binding are the cAMP pathway (through the adenylyl cyclase effector) and the phosphatidylinositol signal pathway (through the phospholipase C effector) [61]. OXR signaling is highly diverse depending on the milieu in which they are operating, and different responses have been observed at different sites [18; 62]. Orexins, via OXRs, activate phospholipase A2, C and D, diacylglycerol lipase, PI3K (phosphatidyl3-kinase)-Akt (protein kinase B), adenylyl cyclase/cAMP, and MAPK (mitogen-activated protein kinases)-ERK (extracellular-signal-regulated kinases) 1/2 and JNK (jun amino-terminal kinases) signaling cascades [18; 63]. The two OXRs may couple to several G-protein species; thus, although the Gq phospholipase C (PLC) pathway plays an important role in many cases [62], the idea that OXR1 couples only to Gq and OXR2 couples to Gq and G\({}_{\text{i/o}}\) needs to be reconsidered [18], and no evidence shows significantly different signaling of the two OXR subtypes [62]. In general, OXRs coupled with Gq proteins stimulate intracellular calcium via PLC [13; 18; 62]. They are also capable of regulating adenylyl cyclase, but this action seems less prominent than coupling to the PLC and calcium cascades [18]. In general, changes in the structure of the receptor after ligands binding [37] trigger a protein kinase C (PKC)-mediated influx of calcium across the plasma membrane via L-type calcium channels [13]. The activation of the calcium channels is related to many other signaling pathways, including the activation of MAPK, especially the ERK p38, cAMP-response element binding protein (CREB), adenylyl cyclase, and PLC [13]. The main responses of activation of OXRs in neurons are the inhibition of K\({}^{+}\) channels and the activation of the Na\({}^{+}\)/Ca\({}^{2+}\) exchanger and non-selective cation channels of unknown identity, although the G protein implicated as the main signal transducer in these cells is still unknown [62]. Both OXRs strongly activate PLC [18], and intracellular calcium stores are released from the endoplasmic reticulum by a PLC-mediated pathway, producing sustained excitation of related neurons [64; 65; 66; 67] and inducing cell responses mainly via Ca\({}^{2+}\) and diacylglycerol-mediated pathways [18]. Orexin B induced ERK1/2 activation through OXR2, predominantly through the Gq/PLC/PKC pathway [68], although this receptor can differentially couple to Gq, G\({}_{\text{i/o}}\), and G\({}_{\text{s}}\) proteins in different tissues [69; 70]. Anyway, PLC activation may be a very central OXR cascade, and the role of PLC might be to produce Ca\({}^{2+}\) elevation or to elevate diacylglycerol for possible PKC activation [18]. Under certain circumstances, the Gq-PLC pathway may take the route to diacylglycerol lipase, leading to the production of the endocannabinoid 2-archidonoyl glycerol and connecting orexins with endocannabinoid signaling [62]. This interaction between orexins and endocannabinoids has been reported, with indirect evidence, for neuronal circuits regulating antinociception and reward seeking, as well as an autocrine mechanism in orexigenic neurons [71]. Orexin activates reward pathways by upregulating the addiction-related neurotransmitters and receptor activity [13]. It has been reported that OXR1 signaling is a part of the dopaminergic-mediated reward circuit, and that the increased orexin signaling (application of orexin A or enhancement of OXR2) induced a glutamate-stimulated effect on alcohol consumption, an activation that promoted drug seeking via a PLC/PKC pathway [13]. Orexins increase the GH-releasing hormone that stimulated GH release through an L-type Ca\({}^{2+}\) current and PKC-mediated signaling pathways [72; 73]. In addition, other authors report that mechanisms involved in the central control of metabolism, such as AMPK, unfolded protein response, and endoplasmic reticulum stress, are related to the control of energy homeostasis by the orexinergic system [42].