Abstract 5419: The relationship between glutamatergic signaling and altered glutamine metabolism in melanoma

Abstract

Abstract Aberrant glutamatergic signaling has been implicated in many cancer types, and is associated with dysregulated growth leading to cellular transformation and tumorigenesis. Our laboratory has previously illustrated the oncogenic properties of a neuronal receptor, metabotropic glutamate receptor 1 (GRM1) in melanocytes. Glutamate is the natural ligand of GRM1 and the major excitatory neurotransmitter in the central nervous system. Our group has demonstrated that glutamate production/release is upregulated in GRM1 expressing melanoma cells, resulting in constitutive activation of GRM1 and GRM1-associated downstream signaling pathways. We hypothesize that this activation of GRM1 in melanoma cells is associated with higher expression of c-Myc and increased enzymatic activity of glutaminase (GLS) converting glutamine to glutamate. We showed that reducing the extracellular glutamate levels by an inhibitor of glutamate release, Riluzole, led to significantly reduce melanoma cell proliferation in vitro and tumor progression in vivo. We also demonstrated that inclusion of CB-839, a potent, selective, and orally bioavailable GLS inhibitor, resulted in a significant inhibition of GRM1-expressing melanoma cell proliferation compared to GRM1 negative melanoma cell lines. Interestingly, we found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1 expressing melanoma cells led to enhanced suppression of cell proliferation in vitro. Additionally, we found that wild type BRAF melanoma cells are more sensitive to CB-839 than mutated BRAF cells while responses to Riluzole were independent of BRAF genotypes. Furthermore, our data indicate that CB-839 acts by reducing the function, not the expression, of GLS. Currently, we are investigating the relationship between GRM1, c-Myc and GLS by genetic and pharmacological approaches, and if this cascade of events is linked with altered glutamine metabolisms described for many human cancers including melanoma. Citation Format: Raj Shah, Andrew Boreland, Suzie Chen. The relationship between glutamatergic signaling and altered glutamine metabolism in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5419. doi:10.1158/1538-7445.AM2017-5419