Metabotropic Glutamate Receptor 1 in African American Prostate Cancer

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DESCRIPTION (provided by applicant): Prostate cancer (PCa) presents with the greatest racial disparity of any cancer in the U.S., with an alarmingly high incidence and mortality rate among African Americans (AAs). AA men with PCa present with higher tumor volume, more advanced stage, higher Gleason grade, higher prostate-specific antigen (PSA), and worse prognosis than Caucasian Americans (CAs). The underlying reasons for such disproportionate ethnic differences may reflect genuine racial differences in cancer biology, socio-cultural differences, or access to health care systems. Recently, we discovered that serum glutamate levels positively correlate with PCa aggressiveness and Gleason score (e8 versus d6) in AAs and CAs. However, glutamate levels were higher in AAs, with primary or metastatic castrate-resistant (CR) PCa than in CAs. Glutamate deprivation or blockade with a glutamate receptor (i.e., GRM1) antagonist significantly decreased growth, migration and invasion and induced apoptosis in PCa cells. We also demonstrated a higher GRM1 expression in MDA-PCa2b (metastatic AA-PCa cell line) than in the E006AA (primary AA-PCa cell line). GRM1 overexpression increased E006AA cell proliferation, migration, and invasion. Our preliminary data show that GRM1 expression is higher in PCa tissues than in normal or benign glands in AAs. Based on these data, we hypothesized that GRM1 expression levels contribute to biological and clinical aggressiveness of PCa in AAs. Our hypothesis will be tested in the following Specific Aims: (1) to determine the association between tissue expression of GRM1 and clinicohistopathological predictors or prognosticators of PCa progression or aggressiveness in AAs; and (2) to determine the association between GRM1 expression levels and invasive and metastatic phenotypes in AA-PCa cells. Data generated from this exploratory study will define biological and/or clinicohistopathological significance or relevance of GRM1 expression in AA-PCa and may prove useful in discriminating clinically or biologically aggressive tumors from indolent (non-aggressive) tumors and minimizing PCa disparity in AAs.