The Role of Metabotropic Glutamate Receptor 1 Dependent Signaling in Glioma Viability.

Glioma refers to malignant central nervous system tumors that have histologic characteristics in common with glial cells. The most prevalent type, glioblastoma multiforme, is associated with a poor prognosis and few treatment options. On the basis of reports of aberrant expression of mGluRl mRNA in glioma, evidence that melanoma growth is directly influenced by glutamate metabotropic receptor 1 (mGluRl), and characterization of beta-arrestin-dependent prosurvival signaling by this receptor, this study investigated the hypothesis that glioma cell lines aberrantly express mGluRl and depend on mGluR1-mediated signaling to maintain viability and proliferation. Three glioma cell lines (Hs683, A172, and U87) were tested to confirm mGluRl mRNA expression and the dependence of glioma cell viability on glutamate. Pharmacologic and genetic evidence is presented that suggests mGluRl signaling specifically supports glioma proliferation and viability. For example, selective noncompetitive antagonists of mGluRl, CPCCOEt and JNJ16259685, decreased the viability of these cells in a dose-dependent manner, and glutamate metabotropic receptor 1 gene silencing significantly reduced glioma cell proliferation. Also, results of an anchorage-independent growth assay suggested that noncompetitive antagonism of mGluRl may decrease the tumorigenic potential of Hs683 glioma cells. Finally, data are provided that support the hypothesis that a beta-arrestin-dependent signaling cascade may be involved in glutamate- stimulated viability in glioma cells and that ligand bias may exist at mGluRl expressed in these cells. Taken together, the results strongly suggest that mGluRl may act as a proto-oncogene in glioma and be a viable drug target in glioma treatment.