@article{0a6e0f53f32c4efca313adc0ddc6f08c,
title = "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 (SLC7A11high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and 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, cancer therapy, cysteine, cystine, ferroptosis, nutrient dependency, xCT",
author = "Pranavi Koppula and Li Zhuang and Boyi Gan",
note = "Funding Information: We apologize to the colleagues whose relevant work cannot be cited in this review due to space limitations. The research in authors{\textquoteright} lab has been supported by The University of Texas MD Anderson Cancer Center, KC180131 from Department of Defense Kidney Cancer Research Program, R01CA181196, R01CA190370, R01CA244144 from the National Institutes of Health (to BG), CPRIT Research Training Grant (RP170067), and Dr. John J. Kopchick Research Award from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (to PK). Funding Information: We apologize to the colleagues whose relevant work cannot be cited in this review due to space limitations. The research in authors? lab has been supported by The University of Texas MD Anderson Cancer Center, KC180131 from Department of Defense Kidney Cancer Research Program, R01CA181196, R01CA190370, R01CA244144 from the National Institutes of Health (to BG), CPRIT Research Training Grant (RP170067), and Dr. John J. Kopchick Research Award from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (to PK). BG wrote the manuscript with additional support from PK and LZ. PK generated all Fig.s. 2DG, 2-deoxyglucose; AAREs, amino acid response elements; AREs, antioxidant response elements; ALOX12, arachidonate 12-lipoxygenase; ?KG, ?-ketoglutarate; ATF4, activating transcription factor 4; CRISPR, clustered regularly interspaced short palindromic repeats; DUB, deubiquitinase; eIF2?, eukaryotic initiation factor 2?; FDA, Food and Drug Administration; FIN, ferroptosis inducer; GCN2, general control non-derepressible-2; GEMMs, genetically engineered mouse models; GLUT, glucose transporter; GPX4, glutathione peroxidase 4; GSH, reduced glutathione; H2Aub, histone 2A mono-ubiquitination; H2Bub, histone 2B mono-ubiquitination; IKE, imidazole ketone erastin; KEAP1, kelch-like ECH-associated protein-1; KO, knockout; mTORC, mechanistic target of rapamycin complex; NRF2, nuclear factor erythroid 2-related factor 2; PDAC, pancreatic ductal adenocarcinomas; PPP, pentose phosphate pathway; PRC1, polycomb repressive complex 1; PR-DUB, polycomb repressive deubiquitinase; PUFA, polyunsaturated fatty acid; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; TCA, tricarboxylic acid; TNBC, triple-negative breast cancer; Tregs, regulatory T-cells; TRP14, thioredoxin-related protein of 14 kDa; Txnrd1, thioredoxin reductase 1; WT, wild-type. Pranavi Koppula, Li Zhuang, and Boyi Gan declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by the any of the authors. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2021",
month = aug,
doi = "10.1007/s13238-020-00789-5",
language = "English (US)",
volume = "12",
pages = "599--620",
journal = "Protein and Cell",
issn = "1674-800X",
publisher = "Springer-Verlag GmbH and Co. KG",
number = "8",
}