Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Department of Chemical Biology, Rutgers University, Piscataway, New Jersey.
Joint Graduate Program in Toxicology, Rutgers University, Piscataway, New Jersey.
Cancer Res. 2019 Apr 15;79(8):1799-1809. doi: 10.1158/0008-5472.CAN-18-1500.
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 and spontaneous metastatic melanoma . 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 and . 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 and tumor progression . 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. SIGNIFICANCE: These findings demonstrate that targeting glutaminolytic glutamate bioavailability is an effective therapeutic strategy for GRM1-activated tumors.
谷氨酸能信号异常与许多癌症类型（包括恶性黑色素瘤）的代谢活性改变有关。以前，我们已经说明了代谢型谷氨酸受体 1（GRM1）在黑素细胞的肿瘤转化和自发性转移性黑色素瘤中的作用。在这项研究中，我们表明自分泌刺激使 GRM1 受体及其下游有丝分裂信号持续激活。GRM1 激活（GRM1）的黑色素瘤表现出谷氨酰胺酶（GLS）的表达显著增加，GLS 催化谷氨酰胺转化为谷氨酸的第一步。在培养的 GRM1 黑色素瘤细胞系 CB-839 中，一种有效的、选择性的、口服生物可利用的 GLS 抑制剂，抑制细胞增殖，而谷氨酸释放抑制剂利鲁唑促进细胞凋亡死亡。CB-839 和利鲁唑联合治疗比单药治疗效果更好，限制了谷氨酸的生物利用度，有效地抑制了肿瘤细胞的增殖和肿瘤进展。恶性黑色素瘤中 GRM1 的过度激活是一种致癌驱动因素，它独立于经典的黑色素瘤原癌基因 BRAF 或 NRAS 发挥作用。总的来说，这些结果表明，GRM1 的表达促进了一种代谢表型，支持增加谷氨酸的产生和自分泌谷氨酸能信号，通过降低谷氨酸的生物利用度和 GLS 依赖性谷氨酰胺到谷氨酸的转化，可以对其进行药理学靶向治疗。意义：这些发现表明，靶向谷氨酰胺分解谷氨酸的生物利用度是针对 GRM1 激活肿瘤的有效治疗策略。
