Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy
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Protein & Cell
REVIEW Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy Pranavi Koppula1,2, Li Zhuang1, Boyi Gan1,2& 1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA & Correspondence: [email protected] (B. Gan) Received July 28, 2020 Accepted August 28, 2020
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 (SLC7A11high) also have to endure the significant cost associated with SLC7A11mediated metabolic reprogramming, leading to glucoseand glutamine-dependency in SLC7A11high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11high 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.
KEYWORDS SLC7A11, xCT, cystine, cysteine, ferroptosis, nutrient dependency, cancer therapy INTRODUCTION Cysteine is a proteinogenic amino acid that has a versatile role in protein synthesis, posttranslational modification, and
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redox maintenance (Stipanuk et al., 2006; Combs and DeNicola, 2019). Cysteine serves as the rate-limiting precursor for glutathione, a tripeptide comprised of three amino acids—cysteine, glutamate, and glycine—and the most abundant cellular antioxidant. Cysteine can also act as an antioxidant itself as well as the precursor for other biomolecules with antioxidant properties, such as taurine and hydrogen sulfide (Stipanuk et al., 2006; Combs and DeNicola, 2019). Intracellular cysteine can be synthesized through de novo biosynthesis (via the transsulfuration pathway) or recycled through protein degradation. However, because cancer cells often experience high levels of oxidative stress (Trachootham et al., 2009; Chio and Tuveson, 2017), cysteine supply via de novo biosynthesis or protein catabolism generally cannot meet the high demand for antioxidant defense in cancer cells; therefore, most cancer cells mainly rely on obtaining cysteine from the extracellular environment through nutrient transporters. The intra- and extra-cellular redox environments are very differen
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