The Role of Glutamate in Promoting Prostate Cancer Cell Proliferation, Motility, Invasiveness and Survival

Abstract

Prostate cancer (PC) is one of the most common cancers affecting men in the western world. Androgen deprivation was the most common approach for treatment of metastatic PC. Unfortunately, this strategy is accompanied with a several side effects such as diabetes and cardiovascular diseases. Moreover, a tumor relapse was indicated in 80-90% of cases, after 1-3 years of treatment, with a life span 1-2 year due to the development of androgen resistant tumors. This study aimed to identify metabotropic glutamate receptor 1 (mGR1) as a possible target for PC therapy. Androgen sensitive PC cell line LNcap were cultured in presence and absence of glutamate (Glu) release inhibitor Riluzole and mGR1 antagonist BAY36-7620. Functional validation of the effect of Glu deprivation on LNcap cell proliferation, motility, invasiveness was conducted using MTT, wound healing and invasion assays, respectively. Molecular validation of Glu signaling and cell apoptosis was conducted using western blot approach. The data revealed a significant effect of glutamate downmodulation on inhibiting LNcap cell proliferation, motility and invasiveness at concentration of 25μM of Riluzole and BAY36-7620. Molecular analysis showed a marked effect of Glu inhibitors on induction of pro-apoptotic markers c-PARP, c-caspases 3, 7 and 9 and inhibition of Akt dependent cell proliferation. In conclusion, in addition to Androgens, Glu plays an essential role in PC cell proliferation, motility, invasiveness and survival.