Abstract 432: xCT inhibition disrupts redox homeostasis in CD44v-expressing tumor cells showing glutaminolytic metabolism in head and neck squamous cell carcinoma

Abstract

Abstract Metabolic changes favoring aerobic glycolysis and glutaminolysis may influence the sensitivity of tumor cells to anticancer drugs. We previously showed that sulfasalazine, an inhibitor of xCT-dependent cystine transport, selectively induces oxidative damage in undifferentiated tumor cells that express CD44 variant (CD44v) at a high level, without affecting CD44v-negative differentiated tumor cells, in head and neck squamous cell carcinoma (HNSCC). However, whether metabolic changes contribute to the xCT dependency of CD44v-expressing HNSCC cells has remained unknown. Here we show that CD44v-expressing HNSCC cells manifest a highly glutaminolytic phenotype and constitutively generate reactive oxygen species through glutamine metabolism pathway, and that xCT plays a key role in maintaining redox homeostasis in these cells. Inhibition of xCT suppressed the consumption of glutamine without affecting that of glucose in these cells, indicating that CD44v-expressing HNSCC cells also rely on xCT for maintenance of glutaminolysis. Furthermore, administration of sulfasalazine, but not that of the anticancer drug cisplatin, selectively depleted CD44v-expressing undifferentiated tumor cells positive for the glutamine transporter ASCT2 in human HNSCC tumors formed in nude mice. Targeting of xCT is thus a potential therapeutic approach for ASCT2-expressing HNSCC tumors in which cellular metabolism is shifted toward enhanced glutaminolysis. Citation Format: Shogo Okazaki, Kenji Tsuchihashi, Oltea Sampetrean, Hideyuki Saya, Osamu Nagano. xCT inhibition disrupts redox homeostasis in CD44v-expressing tumor cells showing glutaminolytic metabolism in head and neck squamous cell carcinoma [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 432. doi:10.1158/1538-7445.AM2017-432