Tsuchihashi Kenji, Okazaki Shogo, Ohmura Mitsuyo, Ishikawa Miyuki, Sampetrean Oltea, Onishi Nobuyuki, Wakimoto Hiroaki, Yoshikawa Momoko, Seishima Ryo, Iwasaki Yoshimi, Morikawa Takayuki, Abe Shinya, Takao Ayumi, Shimizu Misato, Masuko Takashi, Nagane Motoo, Furnari Frank B, Akiyama Tetsu, Suematsu Makoto, Baba Eishi, Akashi Koichi, Saya Hideyuki, Nagano Osamu
Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan.
Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
Cancer Res. 2016 May 15;76(10):2954-63. doi: 10.1158/0008-5472.CAN-15-2121. Epub 2016 Mar 15.
Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. 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. Here, we show that the 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 glutamate, which promotes 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 establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface. Cancer Res; 76(10); 2954-63. ©2016 AACR.
细胞外游离氨基酸通过影响细胞代谢和恶性行为，参与肿瘤与其微环境之间的相互作用。系统xc(-)由xCT和CD98hc亚基组成，作为质膜反向转运体，摄取细胞外胱氨酸以交换细胞内谷氨酸。在此，我们表明表皮生长因子受体（EGFR）与xCT相互作用，从而促进其在人胶质瘤细胞中的细胞表面表达及功能。表达EGFR的胶质瘤细胞因胱氨酸摄取增加而表现出增强的抗氧化能力，同时促进基质侵袭的谷氨酸水平也升高。成像质谱分析还显示，与亲本细胞形成的肿瘤相比，稳定过表达EGFR的人胶质瘤细胞在小鼠体内形成的脑肿瘤含有更高水平的还原型谷胱甘肽。靶向抑制xCT可抑制胶质瘤细胞中EGFR依赖性抗氧化能力的增强，以及肿瘤生长和侵袭性。我们的研究结果确立了EGFR在通过与细胞表面的xCT相互作用促进胶质瘤细胞恶性潜能方面的新功能作用。《癌症研究》；76(10)；2954 - 63。©2016美国癌症研究协会。
