Human Cancer Biology Serum Glutamate Levels Correlate with Gleason Score and Glutamate Blockade Decreases Proliferation, Migration, and Invasion and Induces Apoptosis in Prostate Cancer Cells

Purpose:During glutaminolysis, glutamine is catabolized to glutamate and incorporated into citric acid cycle and lipogenesis. Serum glutamate levels were measured in patients with primary prostate cancer or metastatic castrate-resistant prostate cancer (mCRPCa) to establish clinical relevance. The effect of glutamate deprivation or blockade by metabotropic glutamate receptor 1 (GRM1) antagonists was investigated on prostate cancer cells’ growth, migration, and invasion to establish biologic relevance. Experimental Design: Serum glutamate levels weremeasured in normalmen (n1⁄4 60) and patients with primary prostate cancer (n 1⁄4 197) or mCRPCa (n 1⁄4 109). GRM1 expression in prostatic tissues was examined using immunohistochemistry (IHC). Cell growth, migration, and invasion were determined using cell cytotoxicity and modified Boyden chamber assays, respectively. Apoptosis was detected using immunoblotting against cleaved caspases, PARP, and g-H2AX. Results: Univariate and multivariate analyses showed significantly higher serum glutamate levels in Gleason score 8 than in the Gleason score 7 and in African Americans than in the Caucasian Americans. African Americans with mCRPCa had significantly higher serum glutamate levels than those with primary prostate cancer orbenignprostate.However, inCaucasianAmericans, serumglutamate levelswere similar in normal research subjects andpatientswithmCRPC. IHC showedweakor no expression ofGRM1 in luminal acinar epithelial cells of normal or hyperplastic glands but high expression in primary ormetastatic prostate cancer tissues. Glutamate deprivation or blockade decreased prostate cancer cells’ proliferation, migration, and invasion and led to apoptotic cell death. Conclusions: Glutamate expression is mechanistically associated with and may provide a biomarker of prostate cancer aggressiveness. Clin Cancer Res; 18(21); 5888–901. 2012 AACR.