The Cystine/Glutamate Antiporter System x _c ⁻ in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

The antiporter system xc− imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system xc− is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system xc−, including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system xc−. Moreover, the roles of system xc− in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system xc− inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System xc− is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system xc− in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS. Antioxid. Redox Signal. 18, 522–555. I. Introduction A. Oxidative stress and antioxidant defense B. GSH metabolism C. Glutamate: neurotransmission and neurotoxicity II. The Cystine/Glutamate Antiporter System xc− A. Functional and pharmacological characteristics of system xc− B. The molecular biology of system xc− C. The phylogeny of xCT, the specific subunit of system xc− D. Regulation of system xc− by transcriptional regulation of its specific subunit xCT E. Regulation of system xc− activity by protein trafficking and protein modification F. Regulation of system xc− activity by substrate availability III. Expression of System xc−In Vitro and In Vivo and Its Functional Consequences A. In the absence of disease, system xc− shows a rather restricted expression pattern in vivo B. System xc− is induced in most cultured cells C. The role of system xc− in the regulation of GSH synthesis, the extracellular redox milieu, and extracellular glutamate levels D. Oxidative glutamate toxicity—an in vitro paradigm for neuronal death induced by system xc− inhibition 1. The cell death pathway in oxidative glutamate toxicity 2. Using oxidative glutamate toxicity to identify neuroprotective pathways 3. Using oxidative glutamate toxicity to screen for neuroprotective drugs 4. Oxidative glutamate toxicity in vivo IV. The Role of System xc− in Health and Disease A. System xc−in vivo—lessons from xCT-deficient mice B. The role of system xc− in the immune system and inflammation C. The role of system xc− in cancer and resistance against anti-cancer drugs 1. System xc− is regulated by potentially oncogenic pathways 2. System xc− mediates the infection of cells by oncogenic Kaposi's sarcoma herpesvirus 3. System xc− plays an important role in the multidrug resistance of cancers 4. Inhibition of system xc− reduces cancer cell replication, tissue invasion, and metastasis 5. System xc− expressed in tumor cells may be used as a target for anticancer drug delivery 6. Up-regulation of system xc− in normal cells provides protection against carcinogenesis—a possible role in cancer prevention 7. Synopsis of the role of system xc− in cancer and resistance against anti-cancer drugs D. System xc− and diseases of the eye 1. Studies of system xc− in the retina 2. Studies of system xc− in the lens and cornea 3. Synopsis and future directions for system xc− and diseases of the eye E. The role of system xc− in diseases of the CNS F. The role of system xc− activity in memory and behavior V. Conclusion

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