title: Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer.
abstract: Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G protein-coupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, the therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during the androgen-sensitive (AS) versus the castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (approximately 65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differentially expressed genes with 'interplay between innate and adaptive immune responses' as the top pathway. Quantitative PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil-related cytokines also was elevated in these tumors. GPR30 (GPER1) expression was significantly higher in CR tumors than in AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) expressed a high level of GPR30, whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence, to our knowledge, that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect via neutrophil-infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC.
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Lam
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Ouyang
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of UrologyUniversity of Washington, Seattle, Washington, USACincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USACincinnati Cancer CenterCincinnati, Ohio, USA Department of Environmental HealthUniversity of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267-0056, USADepartment of Pathology and Laboratory MedicineUniversity of Cincinnati Medical Center, Cincinnati, Ohio, USADepartment of PathologyMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USADepartment of MedicineCenter for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USACenter for Environmental GeneticsUniversity of
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D003517:Cyclopentanes / Q000494:pharmacology*; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; C410798:AR protein, human; D000728:Androgens; D014408:Biomarkers, Tumor; D003517:Cyclopentanes; C109584:GPER1 protein, human; D011804:Quinolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled
keywords: androgen deprivation therapy; androgen-repressed gene; metastases; tumor-infiltrating neutrophils