G Protein-Coupled Receptor 75 (GPR75) As a Novel Molecule for Targeted Therapy of Cancer and Metabolic Syndrome

Abstract

In recent years, molecular targeted therapy has attracted more attention from researchers due to its high efficiency and fewer side effects. Researchers are attempting to find more specific ways to treat diseases. It has been found that there are different targets for the treatment of diseases such as cancer, obesity, and metabolic syndrome. It is important to find a potential target in order to lessen the side effects of current treatments. G Protein-coupled receptors (GPCRs) are a large family of transmembrane proteins that are expressed in many organs, leading to the activation of internal signal transduction cascades through the binding of different ligands, including neurotransmitters, peptides, and lipids. Due to the critical role of GPCRs in cells, it could be a potential target. G protein-coupled receptor 75 (GPR75) is a novel member of the GPCR family that has an important role in many diseases, such as obesity, cancer, and metabolic syndrome. Until now, three ligands have been detected for GPR75, including 20-HETE, CCL5, and RANTES. Recent studies suggest that 20-HETE, through GPR75, triggers signaling pathways including PI3K/Akt and RAS/MAPK, leading to a more aggressive phenotype in prostate cancer cells. Additionally, the PI3K/Akt and RAS/MAPK signaling pathways activate NF-κB, which is significant in various pathways of cancer development such as proliferation, migration, and apoptosis. The findings indicate that inhibiting GPR75 in humans leads to an increase in insulin sensitivity and glucose tolerance, as well as a reduction in body fat storage. According to these discoveries, GPR75 could be a potential target for drug treatment of diseases such as obesity, metabolic syndrome, and cancer. In this review, we aimed to discuss the therapeutic impact of GPR75 in cancer, metabolic syndrome, and obesity and underscore the possible pathways.

Keywords: G protein-coupled receptors 75; Metabolic Syndrome; Molecular Targeted Therapy; Obesity; cancer.

Figure 1

GPR75 Tissue Expression based on RPKM (reads per kilo-base per million reads placed)

Figure 2

Binding 20HETE to GPR75 Leads to Dissociation of Gαq11 from GPR75. Gαq11 activates PLC, convertor of PIP2 to IP3 and DAG. IP3 increases cytoplasm Ca2+ through the releasing ERK Ca2+. DAG cooperates with Ca2+ to activate PKC and eventually PI3K/AKT is activated. Another pathway activates NF-KB via MAPK and initiate downstream cascade

Figure 3

CCL5 has Two Receptors Including CCR5 and GPR75. Binding of CCL5 to GPR75 initiate cascade signal pathway which AKT-ERK act as upstream regulator. AKT-ERK triggers MDM2, IKKα, and mTOR resulting in proliferation and differentiation