Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer

    1. Shuk-Mei Ho1,5,7,8
    1. 1Department of Environmental Health, University of Cincinnati Medical Center, Room 128 Kettering Complex, Cincinnati, Ohio 45267‐0056, USA
      2Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
      3Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
      4Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri, USA
      5Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
      6Department of Urology, University of Washington, Seattle, Washington, USA
      7Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA
      8Cincinnati Cancer Center, Cincinnati, Ohio, USA
    1. Correspondence should be addressed to S-M Ho; Email: Shuk-mei.Ho{at}


    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.

    • Revision received 30 September 2014
    • Accepted 6 October 2014
    • Made available online as an Accepted Preprint 6 October 2014
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