Aerobic glycolysis and glutaminolysis are the major hallmarks of cancer cells. During glycolysis and glutaminolysis, glucose is converted to lactate and glutamine to glutamate, respectively. Other than its role as a significant biosynthetic precursor, glutamate metabolism is intimately linked to lipogenesis and androgen biosynthetic pathways. Inhibition of the AR and its signaling pathways remain a key therapeutic target for both androgen-stimulated (AS) and castrate-resistant prostate cancer (CRPCa). One of the hallmarks of PCa cells which are functionally and metabolically linked to glutamate and glycolytic pathways is an increased de novo fatty acid synthesis due to overexpression of the key enzyme, fatty acid synthase (FAS). To assess the clinical relevance of glutamate, we measured serum glutamate levels in normal men (n=60) and patients with primary PCa (n=197) or metastatic-CRPCa (n=109). We recently reported significantly higher serum glutamate levels in Gleason score e 8 compared to Gleason score d 7 which is associated with clinical aggressiveness of PCa. We also found that glutamate receptor GRM1 is overexpressed in primary and metastatic PCa tissues. GRM1 receptor expression in androgen-independent or CRPCa cell lines (e.g., PC-3, DU-145, VCaP) was also higher than in the AS-LNCaP or primary PCa cell line, E006AA. Riluzole, a well-tolerated FDA-approved oral medicine for the treatment amyotropic lateral sclerosis (ALS) and in several active clinical trials for depression, epilepsy, and other benign neurological diseases, has been shown to be a potent pharmacological inhibitor of GRM1. Riluzole decreased proliferation, migration, and invasion and induced apoptosis in both AS and CRPCa cell lines. Our most recent data demonstrated that Riluzole decreases FAS expression in PCa cells. Based on antitumor activities of Riluzole, we hypothesize that Riluzole serves as a novel therapeutic agent for PCa. To test our hypothesis, we will investigate:
(Aim 1) The effect of Riluzole on (i) tumor growth in a subcutaneous castrate-resistant (CR) progression model and (ii) spontaneous metastatic ability of an orthotopic xenograft model.
(Aim 2) Determine the effect of Riluzole on FAS expression and apoptotic markers in primary and metastatic tumors. In this Aim, we will be able to verify our in vitro data by examining the association between Riluzole treatment and FAS expression and fatty acid content in tumor xenografts. In addition, we will investigate the underlying mechanisms by which Riluzole downregulates FAS expression in PCa cells. These preclinical exploratory studies should verify our in vitro data and validate therapeutic efficacy of Riluzole and anti-GRM1 targeted therapy leading to the development of clinical trials using GRM1-blocking agents in PCa patients.
Lipogenic pathways leading to androgen synthesis and androgen receptor-dependent signaling pathways remain as the main targets for treatment in prostate cancer (PCa). There appears to be great unmet needs for the development of more effective therapeutic interventions and selective methods to target androgen biosynthetic pathways. One of the hallmarks of PCa cells which are functionally and metabolically linked to glutamate and glycolytic pathway, is an increased de novo fatty acid synthesis due to overexpression of key enzyme, fatty acid synthase (FAS). Our new data demonstrated that Riluzole, a potent pharmacological inhibitor of glutamate receptor GRM1, decreased growth, migration, and invasion, induced apoptosis, and decreased FAS expression in androgen-stimulated and metastatic castrate-resistant PCa cell lines. In this study, we will investigate the therapeutic efficacy of Riluzole and its association with FAS expression in primary and metastatic tumors in vivo.
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|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|