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Published on: September 3, 2013
Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer
Hung-Ming Lam1, Bin Ouyang1, Jing Chen1
1Department 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.
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.
Insights
G-1 effectively treats castration-resistant prostate cancer (CRPC) by targeting GPR30, an androgen-repressed receptor. This treatment induces neutrophil-driven tumor necrosis, offering a new therapeutic strategy for advanced prostate cancer.
Area of Science:
- Oncology
- Endocrinology
- Immunology
Background:
- Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer with high mortality.
- The therapeutic mechanisms of G-1, a G protein-coupled receptor 30 (GPR30) agonist, and its interaction with androgen in vivo remain unclear.
- GPR30 expression is implicated in prostate cancer progression.
Purpose of the Study:
- To investigate the therapeutic effects of G-1 in androgen-sensitive (AS) versus castration-resistant (CR) prostate cancer models.
- To elucidate the relationship between G-1 treatment, androgen signaling, and the tumor microenvironment in CRPC.
- To assess GPR30 expression levels in clinical prostate cancer specimens.
Main Methods:
- Utilized LNCaP xenograft models to simulate AS and CR prostate cancer phases.
- Administered G-1 and assessed tumor growth, host toxicity, and histological changes (necrosis, neutrophil infiltration).
- Performed global transcriptome profiling and quantitative PCR to analyze gene expression changes, focusing on immune response pathways.
- Investigated GPR30 expression regulation by androgen in cell-based assays and analyzed GPR30 levels in clinical CRPC metastases and primary tumors.
Main Results:
- G-1 inhibited CR tumor growth but not AS tumor growth, with no observable host toxicity.
- CR tumors treated with G-1 exhibited significant necrosis (approx. 65%) and marked intratumoral neutrophil infiltration.
- Transcriptome analysis revealed 'interplay between innate and adaptive immune responses' as a top pathway, with upregulated neutrophil chemokines and cytokines in G-1-treated CR tumors.
- GPR30 expression was significantly higher in CR tumors than AS tumors and is repressed by androgen, with expression reversible by anti-androgen or androgen receptor silencing.
- High GPR30 expression was observed in 80% of CRPC metastases (n=123) compared to 54% of primary PCs (n=232).
Conclusions:
- GPR30 is an androgen-repressed target in prostate cancer.
- G-1 mediates anti-tumor effects in CRPC through neutrophil-infiltration-associated necrosis.
- These findings support GPR30 as a potential therapeutic target for CRPC, warranting further investigation.
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