Gastrin-Releasing Peptide Receptor (GRPR)
The human gastrin-releasing peptide receptor (hGRPR) gene was cloned in 1990 from NIH3T3 cells and located on chromosome X (Xp22.2–Xp22.13). It encodes a seven-transmembrane α-helices G protein-coupled receptor (GPCR) of 384-aa, interacting with large heterotrimeric G proteins of the Gαq and Gα12/ Gα13 families. The main GRPR ligands are represented by bombesin-like peptides (BLPs), including gastrin-releasing peptide (GRP) that is a peptide originally isolated from porcine stomach, synthesized as a precursor of 148-aa (PreproGRP) and post-translationally modified as a mature 27-aa neuropeptide. GRP is the mammalian homolog of the amphibian 14-aa peptide bombesin (BBS), sharing the same C-terminal sequence and binding to the same receptor. Four BLP binding receptor subtypes have been isolated: receptor subtype 1, termed GRPR, which binds BBS and GRP with high affinity; receptor subtype 2 binding neuromedin B; subtype 3 classified as an orphan receptor; and subtype 4, binding amphibian BBS with higher affinity than GRP. In humans, ligands and receptors are widely distributed, and their expression levels are high during embryonic formation, while they decrease at birth, being mainly located in the central nervous system (CNS) and neuroendocrine system (thyroid, pituitary glands, pancreas, adrenal glands) as well as in several peripheral tissues including the gastrointestinal tract, lungs, muscles, urogenital and reproductive system, immune cells, and hematopoietic system. In CNS, BLPs/GRPR function as neurotransmitters to control thermoregulation, feeding behavior, circadian rhythm, memory, as well as social interaction and emotional responses (Roesler et al. 2006); in the gastrointestinal tract, they control the release of gastrointestinal hormones (Jensen et al. 1988); in muscles they regulate smooth muscle cell contraction (Severi et al. 1991), while in epithelial cells they control cell proliferation (Ghatei et al. 1982). Interestingly, the biological effects resulting from the binding of GRPR to its ligand are quite often mediated by the release of secondary peptide hormones, for instance, GRP stimulation of GRPR on gastric G-cells mediates gastrin release and gastric acid secretion from parietal cells (Weigert et al. 1996); GRP stimulation of pancreatic cells modulates amylase secretion (Jensen et al. 1988), whereas BBS activation of M-cells in the small intestine results in the secretion of motilin and regulation of smooth muscle cell contraction (Poitras et al. 1997).
GRPR Expression in Human Diseases
GRP/GRPR dysfunction in CNS disorders (Roesler and Schwartsmann 2012)
Besides CNS disorders, alterations of GRPR signaling have been also described in various inflammatory processes including colonic and gastrointestinal inflammation, arthritis, uveitis, and acute lung inflammation. Moreover, GRP/GRPR expression has been found in lymphocytes, neutrophils, eosinophils, macrophages, and mast cells (Furness et al. 1999), suggesting GRPR as a molecular target for inflammatory disorders, in line with a recent report demonstrating a reduction of proinflammatory cytokines (TNF and IL-1) from activated macrophages in response to specific antagonist of the GRPR (RC-3095) (Dal-Pizzol et al. 2006).
GRPR Expression in Tumors
GRP/GRPR expressing tumors (Laukkanen and Castellone 2016)
Head and neck
Several studies have reported aberrant activation of GRP/GRPR signaling in a substantial fraction of colorectal cancer CRC patients (38–76%) and have correlated this positivity to more invasive behavior for the ability of GRPR to regulate morphological and adhesive properties of CRC through interaction with the cyclooxygenase-2 (Cox2) signaling (Gupta and Dubois 2001; Jensen et al. 2001).
GRPR as a Molecular Target
Because GRP/GRPR signaling is involved in a number of human diseases and in several malignancies, the inhibition of this ligand/receptor complex represents an attractive target for therapy. Several inhibitory approaches have been developed in the past years (Reviewed in Laukkanen and Castellone 2016). The most promising are represented by GRPR antagonists (RC-3095 and RC-3940-II) that have demonstrated a strong anticancer effect in vitro and in vivo when used alone or in combination protocols with other chemotherapeutic agents. Alternative approaches are represented by monoclonal antibodies against BLPs (2A11-mAb) that have demonstrated growth inhibition of lung and squamous cell carcinoma of the head and neck and from antisense oligodeoxynucleotides (ODN) directed against GRPR mRNA, able to reduce proliferation of SCLC cells as well as of other GRP responding cells. Finally, the most innovative therapeutic alternative is represented by the development of nanoparticle-mediated delivery of BBS-GRP/GRPR molecules. BBS conjugated to poly(lactic-co-glycolic acid)(PLGA) nanoparticles targeting delivery of docetaxel (DTX) in GRPR overexpressing cells has been recently successfully tested in breast cancer with encouraging results because of its ability to overcame nonspecific toxicity and to reduce the off-target effects of chemotherapy compounds.
GRP/GRPR complex has been shown to play a crucial role during embryonic development and in a number of health disorders, but due to the lack of selective tools, the therapeutic interest concerning this system has been delayed. Only more recently, with the discovery that GRP/GRPRs are frequently expressed in cancer cells, with a limited distribution in normal tissues, more effort has been put toward the identification of inhibitors that would target these peptides/growth factor receptors alone or in combination with conventional chemotherapies. Among these approaches, receptor antagonists, monoclonal antibodies, and antisense oligonucleotides have shown promising results in animal studies as well as in early clinical trials. The growing interest to identify novel small molecules with increased receptor affinity and to test alternative administration methods (using, for instance, metal nanoparticles with a prolonged half-life and a reduced toxicity for healthy tissues) will provide additional strategies to block the autocrine and/or paracrine neuropeptide activation and offer novel therapeutic weapons for all the disorders where GRP/GRPR activation has been demonstrated, like cancer or CNS disorders.
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