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Lo M, Wang YZ, Gout PWThe x(c) (-) cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 215: 593-602

Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada.
Journal of Cellular Physiology (Impact Factor: 3.87). 06/2008; 215(3):593-602. DOI: 10.1002/jcp.21366
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ABSTRACT The x(c) (-) cystine/glutamate antiporter is a major plasma membrane transporter for the cellular uptake of cystine in exchange for intracellular glutamate. Its main functions in the body are mediation of cellular cystine uptake for synthesis of glutathione essential for cellular protection from oxidative stress and maintenance of a cystine:cysteine redox balance in the extracellular compartment. In the past decade it has become evident that the x(c) (-) transporter plays an important role in various aspects of cancer, including: (i) growth and progression of cancers that have a critical growth requirement for extracellular cystine/cysteine, (ii) glutathione-based drug resistance, (iii) excitotoxicity due to excessive release of glutamate, and (iv) uptake of herpesvirus 8, a causative agent of Kaposi's sarcoma. The x(c) (-) transporter also plays a role in certain CNS and eye diseases. This review focuses on the expression and function of the x(c) (-) transporter in cells and tissues with particular emphasis on its role in disease pathogenesis. The potential use of x(c) (-) inhibitors (e.g., sulfasalazine) for arresting tumor growth and/or sensitizing cancers is discussed.

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    • "Increased reliance on xCT for import of cysteine for glutathione synthesis also suggests that targeting of this receptor will provide greater therapeutic margins than direct inhibition of glutathione synthesis that would be expected to result in wide-ranging toxicities [32]. Thus, xCT is considered an attractive target for cancer [28] [29]. Activation of oncogenes reprogram cancer cells toward aerobic glycolysis to support their proliferation and growth, a phenomenon known as the Warburg effect [2]. "
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    • "System x c -is an intriguing component of excitatory signaling, the study of which may yield insights into the pathology and treatment of CNS diseases. Originally described as a sodiumindependent glutamate transporter (Bannai and Kitamura 1980), system x c -is capable of nonvesicular glutamate release by coupling the uptake of one molecule of cystine to the release of one molecule of glutamate (Bannai 1986; Bridges et al. 2012b; Lo et al. 2008; Piani and Fontana 1994). The Fig. 2 Systemic administration of the system x c -inhibitor sulfasalazine dose-dependently reduces extracellular glutamate levels in the prefrontal cortex. "
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    • "Of them, up-regulation of SLC1A5, SLC7A1, and SLC7A11 were remarkable, possibly leading to the increase of amino acid intake (Table S4). Notably, SLC7A11, which is a cysteine transporter (xCT), confers resistance against oxidative stress and is related to multiple cancers [47]. "
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