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.

Public Health Relevance

The incidences, mortality, and aggressiveness of prostate cancer (PCa) in African American (AA) men are higher than in Caucasians (CAs). We recently discovered that serum glutamate levels positively correlate with PCa aggressiveness and Gleason score (e8 versus d6) and were higher in AAs, with primary or metastatic castrate-resistant PCa than in CAs. Our data show that glutamate receptor-GRM1 expression is higher in PCa tissues than in normal or benign glands in AAs. In this exploratory study, the biological relevance of alterations in GRM1 expression levels will be examined on tumor growth and metastasis in AA-PCa cell lines. To define the clinical significance, we will determine the association between tissue-expression levels of GRM1 and clinicopathological predictors or prognosticators of PCa aggressiveness in AA-men. Data obtained from the proposed studies may prove diagnostic utilities in discriminating between clinically or biologically aggressive tumors and non-aggressive (indolent) tumors and provide novel opportunities using GRM1-antagonist or blocking agent(s) for PCa therapy in AA men.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA183892-01
Application #
8675361
Study Section
Special Emphasis Panel (ZRG1-OBT-Z (55))
Program Officer
Woodhouse, Elizabeth
Project Start
2014-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$221,589
Indirect Cost
$91,089
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Koochekpour, Shahriar; Buckles, Erick; Shourideh, Mojgan et al. (2014) Androgen receptor mutations and polymorphisms in African American prostate cancer. Int J Biol Sci 10:643-51
Ali, Shafat; Shourideh, Mojgan; Koochekpour, Shahriar (2014) Identification of novel GRM1 mutations and single nucleotide polymorphisms in prostate cancer cell lines and tissues. PLoS One 9:e103204
Koochekpour, Shahriar; Willard, Stacey S; Shourideh, Mojgan et al. (2014) Establishment and characterization of a highly tumorigenic African American prostate cancer cell line, E006AA-hT. Int J Biol Sci 10:834-45