PT  - JOURNAL ARTICLE
AU  - Carrie Bowman Dalley
AU  - Barbara Wroblewska
AU  - Barry B. Wolfe
AU  - Jarda T. Wroblewski
TI  - The Role of Metabotropic Glutamate Receptor 1 Dependent Signaling in Glioma Viability
AID  - 10.1124/jpet.118.250159
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.250159
4099  - http://jpet.aspetjournals.org/content/early/2018/07/27/jpet.118.250159.short
4100  - http://jpet.aspetjournals.org/content/early/2018/07/27/jpet.118.250159.full
AB  - Glioma refers to malignant central nervous system tumors that have histological characteristics in common with glial cells. The most prevalent type, glioblastoma multiforme, is associated with a poor prognosis and few treatment options. Based on reports of aberrant expression of mGluR1 mRNA in glioma, evidence that melanoma growth is directly influenced by mGluR1, and characterization of β-arrestin dependent pro-survival signaling by this receptor, this study investigates the hypothesis that glioma cell lines aberrantly express mGluR1 and depend on mGluR1 mediated signaling to maintain viability and proliferation. Three glioma cell lines (Hs683, A172 and U87) were tested to confirm mGluR1 mRNA expression and the dependence of glioma cell viability on glutamate. Pharmacologic and genetic evidence is presented that suggests mGluR1 signaling specifically supports glioma proliferation and viability. For example, selective non-competitive antagonists of mGluR1, CPCCOEt and JNJ16259685, decreased the viability of these cells in a dose dependent manner and GRM1 silencing significantly reduced glioma cell proliferation. Also, results of an anchorage- independent growth assay suggest that noncompetitive antagonism of mGluR1 may decrease the tumorigenic potential of Hs683 glioma cells. Finally, data are provided that support the hypothesis that a β-arrestin dependent signaling cascade may be involved in glutamate- stimulated viability in glioma cells and that ligand bias may exist at mGluR1 expressed in these cells. Taken together, the results strongly suggest that mGluR1 may act as a proto-oncogene in glioma and be a viable drug target in glioma treatment.