Blocking glutamate‐mediated signalling inhibits human melanoma growth and migration

Abstract

Glutamate is an excitatory neurotransmitter that has been shown to regulate the proliferation, migration and survival of neuronal progenitors in the central nervous system through its action on metabotropic and ionotropic glutamate receptors (GluRs). Antagonists of ionotropic GluRs have been shown to cause a rapid and reversible change in melanocyte dendritic morphology, which is associated with the disorganization of actin and tubulin microfilaments in the cytoskeleton. Intracellular expression of microtubule-associated protein (MAP) 2a affects the assembly, stabilization and bundling of microtubules in melanoma cells; stimulates the development of dendrites; and suppresses melanoma cell migration and invasion. In this study, we investigated the relationship between glutamate-mediated signalling and microtubules, cell dendritic morphology and melanoma cell motility. We found that metabotropic GluR1 and N-methyl-d-aspartate receptor antagonists increased dendritic branching and inhibited the motility, migration and proliferation of melanoma cells. We also demonstrated that the invasion and motility of melanoma cells are significantly inhibited by the combination of increased expression of MAP2a and either metabotropic GluR1 or N-methyl-d-aspartate receptor antagonists. Moreover, the blockade of glutamate receptors inhibited melanoma growth in vivo. Collectively, these results demonstrate the importance of glutamate signalling in human melanoma and suggest that the blockade of glutamate receptors is a promising novel therapy for treating melanoma.

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

“…Furthermore, Magnus Karlsson and coworkers have reported that increased glutamate pools in tumors leads to increased leucine formation, a consistent result reflected in this study [42]. The blockade of glutamate receptors has been proposed as a promising novel therapy for treating melanoma [43]. Catalyzed by carbamoyl phosphate synthetase, glutamine is converted to carbamoyl phosphate and then used for pyrimidine metabolism in which uracil, a pyrimidine derivative, is observed evidently upregulated in tumor bearing mice in the present study.…”

1H NMR metabolomics study of metastatic melanoma in C57BL/6J mouse spleen

“…Glutamate signaling in cancer has stimulated extensive research interest recently and has shown great importance in human melanoma development (Namkoong et al 2007; Choi et al 2011; Stepulak et al 2005; Rzeski et al 2001). The blockade of glutamate receptors has been proposed as a promising novel therapy for treating melanoma (Song et al 2012). Suppression of glutamate release can result in decreased cell proliferation in ex vivo and tumorigenesis in vivo as well as migration and invasion of human melanoma (Namkoong et al 2007; Lee et al 2011).…”

Antinociceptive effect of systemically administered dipyrone (metamizol), magnesium chloride or both in a murine model of cancer

“…In fact, inhibition of glutamate release or glutamate receptor activation has proven to decrease growth, migration and invasion, and to induce apoptosis in different types of cancer (Willard and Koochekpour, 2013). Also, the blockade of mGlu1 and the use of NMDA receptor antagonists inhibited melanoma growth (Song et al, 2012). Also, the blockade of mGlu1 and the use of NMDA receptor antagonists inhibited melanoma growth (Song et al, 2012).…”