Rabbit Anti-Human GRM1 (internal) Polyclonal antibody

Aberrant glutamatergic signaling has been implicated in altered metabolic activity in many cancer types, including malignant melanoma. Previously, we have illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. In this study, we showed that autocrine stimulation constitutively activates the GRM1 receptor and its downstream mitogenic signaling. GRM1-activated (GRM1(+)) melanomas exhibited significantly increased expression of glutaminase (GLS), which catalyzes the first step in the conversion of glutamine to glutamate. In cultured GRM1(+) melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, suppressed cell proliferation, while riluzole, an inhibitor of glutamate release, promoted apoptotic cell death in vitro and in vivo. Combined treatment with CB-839 and riluzole treatment proved to be superior to single-agent treatment, restricting glutamate bioavailability and leading to effective suppression of tumor cell proliferation in vitro and tumor progression in vivo. Hyperactivation of GRM1 in malignant melanoma is an oncogenic driver, which acts independently of canonical melanoma proto-oncogenes, BRAF or NRAS. Overall, these results indicate that expression of GRM1 promotes a metabolic phenotype that supports increased glutamate production and autocrine glutamatergic signaling, which can be pharmacologically targeted by decreasing glutamate bioavailability and the GLS-dependent glutamine to glutamate conversion.

Background: Ginsenoside Rg3, a derivative of steroidal saponins abundant in ginseng, has a range of effects on cancer cells, including anti-cell proliferation and anti-inflammation activity. Here, we investigate two long noncoding RNAs (lncRNAs), STXBP5-AS1 and RFX3-AS1, which are hypomethylated and hypermethylated in the promoter region by Rg3 in MCF-7 cancer cells. Methods: The lncRNAs epigenetically regulated by Rg3 were mined using methylation array analysis. The effect of the lncRNAs on the apoptosis and proliferation of MCF-7 cells was monitored in the presence of Rg3 or Korean Red Ginseng (KRG) extract after deregulating the lncRNAs. The expression of the lncRNAs and their target genes was examined using qPCR and Western blot analysis. The association between the expression of the target genes and the survival rate of breast cancer patients was analyzed using the Kaplan-Meier Plotter platform. Results: STXBP5-AS1 and RFX3-AS1 exhibited anti-and pro-proliferation effects, respectively, in the cancer cells, and the effects of Rg3 and KRG extract on apoptosis and cell proliferation were weakened after deregulating the lncRNAs. Of the genes located close to STXBP5-AS1 and RFX3-AS1 on the chromosome, STXBP5, GRM1, RFX3, and SLC1A1 were regulated by the lncRNAs on the RNA and protein level. Breast cancer patients that exhibited a higher expression of the target genes of the lncRNAs had a higher metastasis-free survival rate. Conclusion: The current study is the first to identify lncRNAs that are regulated by the presence of Rg3 and KRG extract and that subsequently contribute to inhibiting the proliferation of cancer cells. (C) 2019 The Korean Society of Ginseng, Published by Elsevier Korea LLC.