Malignant glioma such as glioblastoma is a cancer still difficult to treat. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate, which has been reported to be involved in malignant phenotypes of glioma cells. However, the underlying mechanism of xCT regulation in glioma is not elucidated. Here we show that the epidermal growth factor receptor (EGFR) interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake as well as increased extracellular glutamate which promotes glioma matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells as well as tumor growth and invasiveness. Our findings propose that xCT is a promising therapeutic target in EGFR-overexpressing malignant glioma.

Citation Format: Kenji Tsuchihashi, Shogo Okazaki, Momoko Yoshikawa, Ryo Seishima, Oltea Sampetrean, Nobuyuki Onishi, Hiroaki Wakimoto, Frank Furnari, Eishi Baba, Koichi Akashi, Hideyuki Saya, Osamu Nagano. xCT promotes malignant phenotypes in EGFR-expressing glioma [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 LB-334. doi:10.1158/1538-7445.AM2017-LB-334