xCT, also called SLC7A11, is the light chain component of the cysteine/glutamate amino acid exchange transporter system Xc (1,2). System Xc is composed of two subunits, the light chain (xCT) and the heavy chain (CD98hc, SLC3A2) and functions by cellular uptake of cysteine in exchange for glutamate in a 1:1 ratio (1,2). The human xCT gene is located on chromosome 4q28.3 and is synthesized as a 12-pass transmembrane protein with both the N- and C-terminals located intracellularly (2, 3). xCT is a 501 amino acids (aa) protein with a theoretical molecular weight of 55.4 kDa (3, 4). xCT expression serves many functional purposes in cells including redox balance, ferroptosis, and chemotherapy or cancer drug resistance (1-3, 5-7). Import of cysteine by xCT plays a role in promoting oxidative stress response as cysteine is a precursor for glutathione synthesis (2, 3, 5-7). Glutathione is a cofactor for ROS-detoxifying enzymes, including glutathione peroxidase (GPX), which help defend from cellular ROS-induced damage (2, 3, 5-7). In addition to its antioxidant role, xCT also utilizes glutathione and GPX to inhibit ferroptosis, which is iron-dependent, non-apoptotic cell-death that occurs with overproduction of lipid hydroperoxides (1-3, 5-7). As cancer cells often experience high oxidative stress, it is understandable that xCT is overexpressed in a variety of cancer types, such as acute myeloid leukemia and breast cancer, and affects cancer growth, invasion, metastasis, and prognosis (1-3, 5-7). xCT expression has also been shown to play a role in glutathione-mediated drug resistance during cancer treatment (1,5,7). However, studies have shown that xCT knockdown results in increased tumor cell death, highlighting its suitability as a druggable target (1,5,7). Specifically, the xCT inhibitors Sulfasalazine, an approved anti-inflammatory drug, and Erastin, a small molecule inhibitor, are potential therapeutic modalities for treating a variety of cancers when used in combination with radiotherapy or immunotherapy (1-3, 5-7).
1. Liu, J., Xia, X., & Huang, P. (2020). xCT: A Critical Molecule That Links Cancer Metabolism to Redox Signaling. Molecular therapy : the journal of the American Society of Gene Therapy. https://doi.org/10.1016/j.ymthe.2020.08.021
2. Koppula, P., Zhang, Y., Zhuang, L., & Gan, B. (2018). Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer communications. https://doi.org/10.1186/s40880-018-0288-x
3. Lin, W., Wang, C., Liu, G., Bi, C., Wang, X., Zhou, Q., & Jin, H. (2020). SLC7A11/xCT in cancer: biological functions and therapeutic implications. American journal of cancer research.
4. xCT: Uniprot (Q9UPY5)
5. Koppula, P., Zhuang, L., & Gan, B. (2020). Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein & cell. https://doi.org/10.1007/s13238-020-00789-5
6. Liu, L., Liu, R., Liu, Y., Li, G., Chen, Q., Liu, X., & Ma, S. (2020). Cystine-glutamate antiporter xCT as a therapeutic target for cancer. Cell biochemistry and function. https://doi.org/10.1002/cbf.3581
7. Cui, Q., Wang, J. Q., Assaraf, Y. G., Ren, L., Gupta, P., Wei, L., Ashby, C. R., Jr, Yang, D. H., & Chen, Z. S. (2018). Modulating ROS to overcome multidrug resistance in cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. https://doi.org/10.1016/j.drup.2018.11.001