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.
Highlights
G protein-coupled receptors (GPCRs) are cellsurface molecules that transduce extracellular signals into intracellular effector pathways through the activation of heterotrimeric G proteins [1]
In order to screen orphan GPCRs that are associated with prostate cancer, we queried the Gene Expression Omnibus (GEO) [28] and patent databases [29] for clues of candidate genes
GPR160 mRNA could hardly be detected in RWPE-1 cells, an established cell line derived from normal prostate epithelial cells transfected with a single copy of the human papilloma virus 18 (HPV-18) [31]
Summary
G protein-coupled receptors (GPCRs) are cellsurface molecules that transduce extracellular signals into intracellular effector pathways through the activation of heterotrimeric G proteins [1]. Owing to their special structural features, signal transduction pathways and extensive physiological functions, GPCRs rank the highest success rate among all drug target categories in pharmaceutical development [2]. Signal transduction of GPCRs and crosstalk of downstream signals, including second messengers, Ras and Rho GTPases, mitogen-activated protein kinases (MAP kinases), phosphoinositide-3 kinases (PI3Ks), and numerous associated cytosolic and nuclear targets, contribute to cell growth, survival, differentiation and migration. Understanding the roles that GPCRs play in human malignancies would certainly help the discovery of novel therapeutic agents
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