title: Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression.
abstract: Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs) comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR) functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE) differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC.
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: Nitin
authors.initials: N
authors.lastname: Patel
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Itakura
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, United States of America; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: Shinwu
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, United States of America; Center for Applied Molecular Medicine and University of Southern California Westside Prostate Cancer Center, Los Angeles, United States of America.
authors.forename: Chun-Peng
authors.initials: CP
authors.lastname: Liao
authors.affiliation: University of Southern California /Norris Comprehensive Cancer Center, Los Angeles, United States of America; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: Pradip
authors.initials: P
authors.lastname: Roy-Burman
authors.affiliation: University of Southern California /Norris Comprehensive Cancer Center, Los Angeles, United States of America; Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Zandi
authors.affiliation: University of Southern California /Norris Comprehensive Cancer Center, Los Angeles, United States of America; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: University of Southern California /Norris Comprehensive Cancer Center, Los Angeles, United States of America; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: Jacek
authors.initials: J
authors.lastname: Pinski
authors.affiliation: University of Southern California /Norris Comprehensive Cancer Center, Los Angeles, United States of America; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States of America; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089-9075, United States of America.
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, United States of America; Center for Applied Molecular Medicine and University of Southern California Westside Prostate Cancer Center, Los Angeles, United States of America; University of Southern California /Norris Comprehensive Cancer Center, Los Angeles, United States of America; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States of America; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089-9075, United States of America.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Gross
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, United States of America; University of Southern California /Norris Comprehensive Cancer Center, Los Angeles, United States of America; Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, United States of America; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, United States of America.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Fini
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D055099:Neuroendocrine Cells / Q000187:drug effects / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000728:Androgens; C575059:GPR158 protein, mouse; D011944:Receptors, Androgen; D043562:Receptors, G-Protein-Coupled; D051059:PTEN Phosphohydrolase