Metabotropic Glutamate Receptor 1 and Glutamate Signaling in Human Melanoma

Abstract

Recently, several laboratories have started to investigate the involvement of glutamate signaling in cancer. In previous studies, we reported on a transgenic mouse model that develops melanoma spontaneously. Subsequent studies in these mice identified that the aberrant expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes played a critical role in the onset of melanoma. Confirmation of the etiologic role of GRM1 in melanoma development was shown in a second transgenic line with GRM1 expression under the regulation of a melanocyte-specific dopachrome tautomerase promoter. Ectopic expression of GRM1 was also detected in a subset of human melanoma cell lines and biopsies, suggesting that aberrant expression of GRM1 in melanocytes may contribute to the development of human melanoma. GRM1, a seven-transmembrane domain G protein-coupled receptor, is normally expressed and functional in neuronal cells, and its ligand, glutamate, is the major excitatory neurotransmitter. Human melanoma cells are shown here to release elevated levels of glutamate, implying a possible autocrine loop. Treatment of GRM1-expressing human melanoma cells with a GRM1 antagonist (LY367385 or BAY36-7620) or a glutamate release inhibitor (riluzole) leads to a suppression of cell proliferation as well as a decrease in levels of extracellular glutamate. Treatment of human melanoma cell xenografts with riluzole for 18 days via p.o. gavage or i.v. injection leads to inhibition of tumor growth by 50% in comparison with controls. These data suggest the importance of glutamate signaling in human melanoma and imply that the suppression of glutamate signaling may be a new target for melanoma therapy. [Cancer Res 2007;67(5):2298-305]

Metastatic Melanoma Induced Metabolic Changes in C57BL/6J Mouse Stomach Measured by 1H NMR Spectroscopy

“…This is confirmed by observed elevation of glutamine, alanine, citrate, asparagine, and decreased hypoxanthine in the tumor bearing mice which are intermediates of the pyrimidine metabolism, the pyruvate metabolism, the TCA cycle, the glutamate metabolism, and the purine metabolism, respectively. Glutamate signaling in cancer has stimulated extensive research interest recently and has shown great importance in human melanoma development [37][38][39][40]. Increased glutamate concentration has also been reported by previous studies as a common phenomenon in tumors [41].…”

New Approaches to Melanoma Treatment: Checkpoint Inhibition with Novel Targeted Therapy

“…Riluzole functions by inhibiting glutamate release from neurons and noncompetitively blocking its uptake by post-synaptic neurons, therefore preventing neuronal glutamate toxicity [14]. Our group showed that Riluzole could disrupt glutamatergic signaling in tumor cells by disrupting glutamate release to the extracellular environment of mGluR1 expressing melanoma cells, limiting the availability of the ligand to maintain receptor activation [15]. One consequence of reduced extracellular glutamate is a decrease in cell growth, as has been shown for many transformed cells including melanoma [16].…”

Melanoma from Molecular Pathways to Clinical Treatment: An Up to Date Review

“…It has been observed that ectopic expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes is sufficient to induce spontaneous melanoma development in vivo and transformation in vitro [37,38]. Moreover; the ectopic expression of GRM1 mediated melanoma agenesis is independent of the genotype of either BRAF or NRAS [39]. Until now the mechanism by which the aberrant expression of glutamate receptor 1 in melanocytes leads to oncogenesis remains unknown.…”