Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

Abstract

The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11^high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucoseand glutamine-dependency in SLC7A11^high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11^high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and-independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.

Key words： SLC7A11; xCT; cystine; cysteine; ferroptosis; nutrient dependency; cancer therapy

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