The EGF Receptor Promotes the Malignant Potential of Glioma by Regulating Amino Acid Transport System xc(-).
The EGF Receptor Promotes the Malignant Potential of Glioma by Regulating Amino Acid Transport System xc(-).
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DOI：
10.1158/0008-5472.can-15-2121
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发表时间：
2016-05-15
期刊：
影响因子：
11.2
通讯作者：
Nagano O
中科院分区：
文献类型：
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作者：
Tsuchihashi K;Okazaki S;Ohmura M;Ishikawa M;Sampetrean O;Onishi N;Wakimoto H;Yoshikawa M;Seishima R;Iwasaki Y;Morikawa T;Abe S;Takao A;Shimizu M;Masuko T;Nagane M;Furnari FB;Akiyama T;Suematsu M;Baba E;Akashi K;Saya H;Nagano O
细胞外游离氨基酸通过影响细胞代谢和恶性行为，促进肿瘤与其微环境的相互作用。Xc系统(−)由Xct和CD98hc两个亚基组成，作为质膜逆向转运蛋白参与胞外半胱氨酸的摄取以换取胞内谷氨酸。在这里，我们发现表皮生长因子受体(EGFR)与XCT相互作用，从而促进其在人脑胶质瘤细胞中的细胞表面表达和功能。表达EGFR的胶质瘤细胞既表现出由于摄取胱氨酸增加而增强的抗氧化能力，也表现出促进基质侵袭的谷氨酸增加。成像质谱仪还显示，与亲代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瘤含有更高水平的还原型谷胱甘肽。XCT的靶向抑制抑制了EGFR依赖的胶质瘤细胞抗氧化能力的增强，以及肿瘤的生长和侵袭性。我们的发现确立了EGFR通过与细胞表面的XCT相互作用来促进胶质瘤细胞恶性潜能的新功能。
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 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 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.