Glutamate is extensively involved in metabolic and oncogenic pathways. Univariate and multivariate analyses showed that serum glutamate levels directly correlated with Gleason score (≤6 vs. ≥8) and primary prostate cancer (PCa) aggressiveness. Compared with Caucasian Americans, serum glutamate levels were higher in African Americans with metastatic castrate-resistant PCa than in the patients with primary tumors. Glutamate deprivation or blockade with pharmacological inhibitors of glutamate release or metabotropic glutamate receptor 1 (GRM1) decreased growth, migration and invasion, and induced apoptosis in both androgen-stimulated and androgen-independent PCa cells. Immunohistochemical staining showed GRM1 overexpression in primary or metastatic PCa tissues. These data highlight the potential of glutamate as a biomarker of aggressiveness in primary PCa and target its metabolic and signaling activities for therapeutic interventions.

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