Abstract 1309: Targeting GluN2C ion channels as a promising approach in the treatment of melanoma

Abstract

Abstract Ion channels are pore-forming integral membrane proteins that are known to have an impact on all hallmarks of cancer. Due to their expression on the surface of the cells, ion channels provide a distinct therapeutic target with more facilitated access from the extracellular milieu. NMDA receptors are a subtype of ligand-gated ion channels that express unique features including high calcium permeability as well as the requirement for binding of glutamate and the co-agonist glycine in order to be activated. Here we show that a glutamate ionotropic NMDA (N-methyl-D-aspartate) type ion channel, GluN2C is critically required for survival of human melanoma cells. Publicly available microarray data from Gene Expression Omnibus (GEO) were acquired in order to identify the differentially expressed ion channel genes in 127 melanoma patient samples relative to benign nevi or human epidermal melanocytes. Data exists into two major cohorts: First cohort consisted of 18 benign nevi and 45 melanoma (GSE3189), while second cohort contained 8 melanocytes and 82 melanoma (GSE29377). A bioinformatics approach was undertaken to determine commonly upregulated ion channels between the two cohorts. Subsequently, functional enrichment analysis along with pathway evaluation of these genes revealed GluN2C as a novel candidate for further investigation in this study. Upregulation of GluN2C was confirmed in a panel of melanoma cell lines and fresh melanoma isolates. Strikingly, silencing of GluN2C markedly reduced viability and clonogenicity in melanoma cells. Consistently, a pharmacological inhibitor of GluN2C potently killed melanoma cells with minimal effects on melanocytes and fibroblasts. Killing of melanoma cells by inhibition of GluN2C was not due to induction of apoptosis, since a general caspase inhibitor Z-VAD-FMK failed to rescue cells from dying. In contrast, the late stage autophagy inhibitor Bafilomycin A1 blocked the GluN2C induced cell death suggesting that killing of melanoma cells following inhibition of GluN2C is in part associated with induction of autophagy. Collectively, these results uncover a potential role for GluN2C ion channels in the pathogenesis of melanoma and suggest that these ion channels may constitute a promising target for melanoma treatment. Citation Format: Hessam Tabatabaee, Yuchen Feng, Hamed Yari, Ting La, Simonne Sherwin, Lei Jin, Rebecca Lim, Alan Brichta, Xu Dong Zhang. Targeting GluN2C ion channels as a promising approach in the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1309.