Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510060, China; Metabolic Innovation Center, Sun Yat-sen University Zhongshan School of Medicine, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510060, China.
Mol Ther. 2020 Nov 4;28(11):2358-2366. doi: 10.1016/j.ymthe.2020.08.021. Epub 2020 Sep 2.
System x cystine/glutamate antiporter, composed of a light-chain subunit (xCT, SLC7A11) and a heavy-chain subunit (CD98hc, SLC3A2), is mainly responsible for the cellular uptake of cystine in exchange for intracellular glutamate. In recent years, the xCT molecule has been found to play an important role in tumor growth, progression, metastasis, and multidrug resistance in various types of cancer. Interestingly, xCT also exhibits an essential function in regulating tumor-associated ferroptosis. Despite significant progress in targeting the system x transporter in cancer treatment, the underlying mechanisms still remain elusive. It is also unclear why solid tumors are more sensitive to xCT inhibitors such as sulfasalazine, as compared to hematological malignancies. This review mainly focuses on the role of xCT cystine/glutamate transporter in regard to tumor growth, chemoresistance, tumor-selective ferroptosis, and the mechanisms regulating xCT gene expression. The potential therapeutic implications of targeting the system x and its combination with chemotherapeutic agents or immunotherapy to suppress tumor growth and overcome drug resistance are also discussed.
系统 x 胱氨酸/谷氨酸反向转运体由轻链亚基（xCT，SLC7A11）和重链亚基（CD98hc，SLC3A2）组成，主要负责细胞摄取胱氨酸以换取细胞内的谷氨酸。近年来，xCT 分子被发现在各种类型的癌症中对肿瘤生长、进展、转移和多药耐药性起着重要作用。有趣的是，xCT 在调节肿瘤相关的铁死亡中也具有重要功能。尽管在癌症治疗中靶向系统 x 转运体方面取得了显著进展，但潜在的机制仍不清楚。也不清楚为什么与血液系统恶性肿瘤相比，固体肿瘤对 xCT 抑制剂（如柳氮磺胺吡啶）更敏感。本综述主要关注 xCT 胱氨酸/谷氨酸转运体在肿瘤生长、化疗耐药、肿瘤选择性铁死亡以及调节 xCT 基因表达的机制中的作用。还讨论了靶向系统 x 及其与化疗药物或免疫疗法联合抑制肿瘤生长和克服耐药性的潜在治疗意义。
