Background. Peptidergic GPCR systems are broadly distributed in the human body and regulate numerous physiological processes by activating complex networks of intracellular biochemical events responsible for cell regulation and survival. Excessive stimulation, ill-function, or blockade of GPCRs produces cell disturbances that may cause disease should compensatory mechanisms not suffice. Methods and Results. Revision of updated experimental research provided an evident relationship associating peptidergic GPCR malfunction with tumor formation and maintenance resulting from uncontrolled cell proliferation and migration, colonization, inhibition of apoptosis or altered metabolism, and increased angiogenesis in tumoral tissues. Conclusion. Determination of the implication of GPCR peptide signaling in specific neoplasia is crucial to designing tailored pharmacological treatments to counteract or dismantle the origin of the signaling circuitry causing cellular disruption. In some cases, particular ligands for these receptors may serve as concomitant treatments to aid other pharmacological or physical approaches to eradicate neoplasias.
The word “cancer” refers to several complex diseases with various etiological factors acting alone or combined, including genetic background/predisposition, environmental influences, aging, hormonal factors, and lifestyle choices. These factors can trigger abnormal biochemical processes and disrupt the cell’s available compensatory mechanisms against damage. If the cells cannot recover from these disruptions, tumors can be generated and progress. Each neoplasia has distinct characteristics based on the type of cell and tissue involved and the specific molecular events and transcriptional programs affected. By studying the biochemical processes for every kind of tumor, we may uncover new biochemical incidences and new opportunities for developing targeted therapies to combat these diseases.
G-protein-coupled receptors (GPCRs) form an extensive family of proteins (more than 800) that convey extracellular chemical or sensory information to trigger intracellular changes affecting short-term intermediary metabolic events and long-term gene expression programs through signaling cascades. GPCRs participate in numerous biochemical events associated with physiopathological processes, including cell transformation, apoptosis, growth, and migration.
Different classification criteria categorize GPCRs into several families or groups. Approximately 350 GPCRs function as non-sensory receptors, processing substances such as amines, peptides, proteins, lipids, ions, nucleotides, or hydroxycarboxylic acids. The remaining roughly 450 GPCRs respond to sensory stimuli, including odors, tastes, photons, or pheromones. Based on sequence homology and functional resemblance, GPCRs are included in eight classes, six of which are present in humans. These include class A (rhodopsin), class B (secretin and adhesion), class C (glutamate), class T (taste), class O (orphans), class E (frizzled/smoothened), and classes D (fungal mating pheromone receptors) and E (cAMP receptors) absent in vertebrates.
Several GPCRs are presently therapeutic targets for numerous pathological conditions, including cardiovascular, chronic inflammation, pain, or cancer pathologies. The weaponry of therapeutic compounds includes synthetic ligands acting on the receptor as molecules displaying full agonism (triggering maximal signal), partial agonism (eliciting activity below the maximum response), inverse antagonism (inhibition of constitutive receptor activity), and neutral antagonism (the constitutive receptor activity is not changed). Other drugs not binding at the orthosteric but at an allosteric site (outside or within the transmembrane helices) are PAMS (positive allosteric modulators) and NAMS (negative allosteric modulators), which activate or inhibit, respectively, the responses raised by orthosteric ligands. Furthermore, the list grows with the so-called bitopic ligands (binding both the orthosteric and the allosteric sites within the GPCR).
Approximately 90 class A and 20 class B GPCRs bind and process around 180 peptide signals. The majority of GPCR-binding peptides belong to class A (for example, receptors for opioids, tachykinins, galanin, neuropeptide Y, orexin, cholecystokinin, bradykinin, somatostatin, endothelin, neurotensin, bombesin, vasopressin, kisspeptin, thyrotropin-releasing hormone, melanocortin, or apelin). A few GPCR class B (secretin) include receptors for glucagon, secretin, corticotropin-releasing factor, parathyroid, vasoactive intestinal peptide, calcitonin, or pituitary adenylate cyclase-activating peptide.
The interaction between peptides and GPCRs is intricate. It encompasses various possibilities, such as one peptide binding to one GPCR, one peptide binding to multiple GPCRs, or multiple peptide ligands binding to multiple GPCRs. This complexity is further heightened by many GPCRs being classified as orphan receptors, with their corresponding peptide activations yet to be identified and confirmed.
This report reviews recent evidence regarding the fine structure, dynamic conformations, and potential mechanisms of action of eight peptidergic GPCRs in tumorigenesis. It also discusses the examination of these systems as pharmacological targets.
Several natural peptides bind with different affinities and activate specific GPCRs with varied localization, triggering a complex network of intracellular signals that control essential cell activity in short-, mid-, and long-term periods. Peptidergic GPCR systems share common properties concerning their broad distribution and shared signaling pathways regulating an array of pleiotropic cell responses affecting vital physiology. We focus on advances concerning eight GPCR peptidergic systems and their relationship with tumorigenesis and expansion. Additionally, we describe some synthetic and specific activating or silencing compounds modulating peptidergic GPCR signaling that may be valuable tools for treating some types of cancer alone or as concomitant measures. The systems comprising the main endogenous ligands and their respective GPCRs are schematically shown in Figure 1.
Natural peptide ligands for eight representative GPCRs. The lines indicate the binding affinity (in different degrees) of peptides for the receptor type. The figure is based on data on pairing peptides and GPCRs reported by Foster et al. Abbreviations: AM2/IMD, adrenomedullin/intermedin; AMY, amylin; APLNR, apelin receptor; CALCR, calcitonin receptor; CALCRL, calcitonin receptor-like; α-CGRP, alpha-calcitonin gene-related peptide; CRHR, corticotrophin releasing hormone receptor; CT, calcitonin; DOPR, delta-opioid receptor; ELA, elabela; GALR, galanin receptor; GPR151, G-protein-coupled receptor 151; KOPR, kappa opioid receptor; Leu-Enk, leucine-enkephalin; Met-Enk, methionine-enkephalin; MOPR, mu-opioid receptor; NKA, neurokinin A; NKB, neurokinin B; NKR, neurokinin receptor; NPYR, neuropeptide Y receptor; NTSR, neurotensin receptor; PP, pancreatic peptide; PYY, peptide YY; PrRP, prolactin-releasing peptide; RFRP, R(Arg) F(Phe)-amide-related peptide SF11, [N-(4-ethoxyphenyl)-4-(hydroxydiphenylmethyl)-1-piperidinecarbothioamide]; SP, substance P; UCN, urocortin.
Several opioid peptides (for instance, enkephalins, endorphins, or dynorphins) and three main types of opioid receptors, mu (MOPR), delta (DOPR), and kappa (KOPR), form the endogenous opioid system, a primary regulator of intrinsic analgesia, cardiovascular responses, gastrointestinal and hepatic function, respiration, thermoregulation, or immunological reactions (see the recent review series by).
The tachykinin system comprises three receptors, namely neurokinin 1, 2, and 3 (NK-1R, NK-2R, and NK-3R), and three main natural ligands, substance P (SP), neurokinin A, and neurokinin B, showing different affinities for the receptors. Also, hemokinin-1 is a natural ligand for NK-1R in peripheral tissues. The tachykinin system is widely distributed in the nervous system and other non-neural cells and tissues and influences numerous physiological functions, such as smooth muscle contraction, cell proliferation, pain, inflammation, or tissue regeneration.
Four neuropeptide Y (NPY) receptors, NPYR 1, 2, 4, and 5, and a handful of peptide ligands with different affinities for the receptors coordinate multiple activities (analgesia, angiogenesis, allergy responses, inflammation mechanisms, or energy homeostasis) from their ubiquitous presence within the human body.
The galanin and GPR151 systems include two ligands, galanin and galanin-like peptide, activating three galanin receptor types: GALR1, GALR2, and GALR3. The galanin system is distributed widely in neural and non-neural tissues and impacts many physiological processes, from pain to metabolism, innate immunity, and inflammation coordination, involved in brain and gastrointestinal function. A galanin-binding receptor, GPR151, previously considered an orphan GPCR, exhibits high structural similarity with galanin receptors and influences metabolic routes controlling glucose homeostasis and trigeminal neuropathic pain. However, it is still unclear and requires further elucidation whether galanin behaves as a proper functional endogenous ligand for GPR151 in CNS structures and the precise role of the GPR151 receptor system.
The calcitonin system is made up of two secretin GPCRs, CACRL (calcitonin receptor-like) and CALCR (calcitonin receptor), regulated by receptor-activity modulating proteins (RAMPs).
