xCT (Slc7a11) RegulationL Lessons from Cancer Research

xCT (Slc7a11) RegulationL Lessons from Cancer Research

Alvin Sherman Library

xCT is an amino acid antiporter that imports cystine in exchange for glutamate with a 1:1 ration in a concentration-dependent manner. Once inside the cell, cystine is quickly reduced to cysteine, the rate-limiting substrate for the main cellular antioxidant, glutathione. The function of xCT has been highlighted by the discovery of a new type of cell death, known as ferroptosis. Ferroptosis is a distinctive form of programmed cell death triggered by lipid peroxidation and the accumulation of reactive oxygen species, leading to cell damage and death. Numerous classes of cancers have shown overexpression of xCT, which correlates with worse outcomes and therapy-resistant tumors due to xCT's antioxidant and ferroptosis-defense functions. The mechanism by which cancer cells upregulate xCT expression, and whether different types of cancers employ identical molecular mechanisms, has not been systematically studied. To answer these questions, we performed a systematic review aimed to consolidate the regulatory mechanisms governing xCT expression. This review encompassed 89 publications, identified through the PubMed database and keyword searches for terms including xCT, Slc7a11 (gene name), and cystine/glutamate antiporter, and screened for regulation of expression mechanisms as needed. The articles were then categorized into six levels of molecular regulation: epigenetic, transcriptional, post-transcriptional, translational, post-translational, and protein-protein interactions/cell localization. We found that xCT is regulated by essentially all known molecular mechanisms, many of which are activated in response to stress. Overall, our work highlights the role of xCT in regulating ferroptosis and the breadth of axes through which its expression can be modulated.

*Both authors contributed equally.