G protein-coupled receptor GPR160 is associated with apoptosis and cell cycle arrest of prostate cancer cells

Abstract

G protein-coupled receptors (GPCRs) represent the largest membrane protein family implicated in the therapeutic intervention of a variety of diseases including cancer. Exploration of biological actions of orphan GPCRs may lead to the identification of new targets for drug discovery. This study investigates potential roles of GPR160, an orphan GPCR, in the pathogenesis of prostate cancer. The transcription levels of GPR160 in the prostate cancer tissue samples and cell lines, such as PC-3, LNCaP, DU145 and 22Rv1 cells, were significantly higher than that seen in normal prostate tissue and cells. Knockdown of GPR160 by lentivirus-mediated short hairpin RNA constructs targeting human GPR160 gene (ShGPR160) resulted in prostate cancer cell apoptosis and growth arrest both in vitro and in athymic mice. Differential gene expression patterns in PC-3 cells infected with ShGPR160 or scramble lentivirus showed that 815 genes were activated and 1193 repressed. Functional annotation of differentially expressed genes (DEGs) revealed that microtubule cytoskeleton, cytokine activity, cell cycle phase and mitosis are the most evident functions enriched by the repressed genes, while regulation of programmed cell death, apoptosis and chemotaxis are enriched significantly by the activated genes. Treatment of cells with GPR160-targeting shRNA lentiviruses or duplex siRNA oligos increased the transcription of IL6 and CASP1 gene significantly. Our data suggest that the expression level of endogenous GPR160 is associated with the pathogenesis of prostate cancer.

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer

“…Among the GPCRs, orphan GPCRs have high potential as therapeutic targets . Some orphan GPCRs, such as GPRC6A and GPR160, are involved in prostate cancer cell proliferation and disease progression . However, the significance of other orphan GPCRs in prostate cancer is elusive.…”

“…11 Some orphan GPCRs, such as GPRC6A and GPR160, are involved in prostate cancer cell proliferation and disease progression. 12,13 However, the significance of other orphan GPCRs in prostate cancer is elusive. In our study, we sought to identify orphan GPCRs that could serve as novel therapeutic target molecules for progressive prostate cancer.…”

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

“…These GPCRs, which are normally expressed in fully differentiated, post-mitotic neuronal cells, are able to induce cellular oncogenic transformation when introduced to an ectopic environment of proliferating cells and activated by agonist 7,8 . In addition to oncogenes and tumorsuppressor genes essential for cancer initiation and progression, autocrine and/or paracrine secretion of GPCR-activating molecules and their downstream signaling events affect tumor growth, survival, and metastasis 1,[9][10][11][12][13][14] .…”

“…These GPCRs, which are normally expressed in fully differentiated, post-mitotic neuronal cells, are able to induce cellular oncogenic transformation when introduced to an ectopic environment of proliferating cells and activated by agonist 7,8 . In addition to oncogenes and tumorsuppressor genes essential for cancer initiation and progression, autocrine and/or paracrine secretion of GPCR-activating molecules and their downstream signaling events affect tumor growth, survival, and metastasis 1,[9][10][11][12][13][14] .Olfactory receptors (ORs) are the largest family of GPCRs present in the olfactory epithelium but are also found in various ectopic or non-olfactory locations such as prostate, heart, placenta, embryo, erythroid cells, spleen, kidney, gut, tongue, and carotid body [15][16][17] . Some ectopic ORs also play roles in chemotaxis 18 , muscle regeneration 19 , blood pressure regulation 20 , and hypoxia response 21 .OR51E2, or Prostate Specific G-protein Receptor (PSGR), is one of the most highly conserved and broadly expressed ectopic ORs 22-24 .…”

GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors

“…GPR160 and GPRC5A, two frequently overexpressed GPCRs, are orphan receptors that influence the malignant 12 phenotype. Knockdown of GPR160 in prostate cancer cells increases apoptosis and growth arrest [36]. It has 13 been suggested that GPRC5A is an oncogene that promotes proliferation, migration and colony formation of 14 PDAC cells [11,12].…”