TY - JOUR TI - GRM1, a potential target for human melanoma DO - https://doi.org/doi:10.7282/T36M35H3 PY - 2013 AB - The survival rate for patients with advanced metastasis ranges from 2 to 8 months with prolonged survival rates of 5% after 5 years. Targeted therapies have emerged as a paradigm for cancer treatments with the inhibition of multiple signaling pathways required to achieve greater successes in pre-clinical and clinical settings. Recent studies have demonstrated that disrupting the glutamatergic system yields promising therapeutic benefits in several cancers [1, 2, 3, 4]. The impediment of glutamate signaling in several of these cancer cell types activated apoptosis leading to decreased tumor cell proliferation and survival in vitro and in vivo. The amino acid, glutamate, is produced rapidly in tumor cells by the conversion of glutamine for use in protein and nucleotide synthesis, ATP production, and expulsion of excess carbon resulting from increased glucose metabolism (Warburg effect) in cancer cells. More recently, aberrant glutamate signaling has been shown to play a role in the transformation and maintenance of various cancer types, including melanoma. Glutamate secretion from these cells has been found to stimulate regulatory pathways that control tumor growth, proliferation and survival in vitro and in vivo. Our group showed that treatment of human melanoma with the glutamate release inhibitor, riluzole, caused a decrease in extracellular concentrations of glutamate in correlation with arrest at the G2/M phase of the cell cycle, followed by apoptotic cell death. Despite these observations, the precise mechanisms through which riluzole hampers melanoma cell survival remain to be elucidated. The present study begins to unravel the modes of action of riluzole in in vitro cultured melanoma cells. We identified a previously unknown consequence in cells treated with riluzole, DNA damage. Furthermore this observation was detected exclusively in melanoma cells expressing metabotropic glutamate receptor 1 (GRM1). Based on these two observations, we hypothesize that suppression of glutamate export from within the cells causes a disruption of intracellular homeostasis of glutamate/cystine exchange by the intracellular accumulation of unreleased glutamate. The limited amount of cystine results in a decrease of available glutathione (GSH) potentially increasing the levels of intracellular reactive oxygen species (ROS) followed by a rise in DNA damage. KW - Toxicology KW - Melanoma--Research KW - Melanoma--Treatment KW - DNA ligases LA - eng ER -