The xc− cystine/glutamate antiporter: A potential target for therapy of cancer and other diseases

Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada.
Journal of Cellular Physiology (Impact Factor: 3.84). 06/2008; 215(3):593-602. DOI: 10.1002/jcp.21366
Source: PubMed


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.

Download full-text


Available from: Yuzhuo Wang,
258 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Reprogramming of energy metabolism is one of the emerging hallmarks of cancer. Up-regulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus, targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here, we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient-derived pancreatic xenograft model. Lentiviruses expressing short hairpin RNAs (shRNAs) targeting 12 different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times, and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including carbonic anhydrase IX (CAIX), monocarboxylate transporter 4, and anionic amino acid transporter light chain, xc- system (xCT) were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation because shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient-derived pancreatic tumor model. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 06/2015; 144(6). DOI:10.1016/j.neo.2015.05.001 · 4.25 Impact Factor
  • Source
    • "Expression of xCT on the cell membrane is essential for the uptake of cystine required for synthesis of intracellular glutathione (GSH), an anti-oxidant that plays an important role in maintaining the intracellular redox balance (Bannai, 1986; Patel et al., 2004). For most cancer cells, the uptake of cystine/cysteine from the microenvironment is crucial for growth and viability (Lo et al., 2008). Therefore, xCT is highly expressed by a variety of malignant tumors such as lymphoma, glioma, breast carcinoma, and prostate cancer (Gout et al., 2001; Narang et al., 2003; Chung et al., 2005; Doxsee et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Expression of xCT, a component of the xc (-) amino-acid transporter, is essential for the uptake of cystine required for intracellular glutathione (GSH) synthesis and maintenance of the intracellular redox balance. Therefore, xCT plays an important role not only in the survival of somatic and immune cells, but also in other aspects of tumorigenesis, including the growth and malignant progression of cancer cells, resistance to anticancer drugs, and protection of normal cells against oxidative damage induced by carcinogens. xCT also functions as a factor required for infection by Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS) and other lymphoproliferative diseases associated with HIV/AIDS. In spite of these advances, our understanding of the role of xCT in the pathogenesis of infectious diseases is still limited. Therefore, this review will summarize recent findings about the functions of xCT in diseases associated with microbial (bacterial or viral) infections, in particular KSHV-associated malignancies. We will also discuss the remaining questions, future directions, as well as evidence that supports the potential benefits of exploring system xc (-) as a target for prevention and clinical management of microbial diseases and cancer.
    Frontiers in Microbiology 02/2015; 6:120. DOI:10.3389/fmicb.2015.00120 · 3.99 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gaps in our understanding of glutamatergic signaling may be key obstacles in accurately modeling complex CNS diseases. System xc (-) is an example of a poorly understood component of glutamate homeostasis that has the potential to contribute to CNS diseases. This study aims to determine whether system xc (-) contributes to behaviors used to model features of CNS disease states. In situ hybridization was used to map mRNA expression of xCT throughout the brain. Microdialysis in the prefrontal cortex was used to sample extracellular glutamate levels; HPLC was used to measure extracellular glutamate and tissue glutathione concentrations. Acute administration of sulfasalazine (8-16 mg/kg, IP) was used to decrease system xc (-) activity. Behavior was measured using attentional set shifting, elevated plus maze, open-field maze, Porsolt swim test, and social interaction paradigm. The expression of xCT mRNA was detected throughout the brain, with high expression in several structures including the basolateral amygdala and prefrontal cortex. Doses of sulfasalazine that produced a reduction in extracellular glutamate levels were identified and subsequently used in the behavioral experiments. Sulfasalazine impaired performance in attentional set shifting and reduced the amount of time spent in an open arm of an elevated plus maze and the center of an open-field maze without altering behavior in a Porsolt swim test, total distance moved in an open-field maze, or social interaction. The widespread distribution of system xc (-) and involvement in a growing list of behaviors suggests that this form of nonvesicular glutamate release is a key component of excitatory signaling.
    Psychopharmacology 05/2014; 231(24). DOI:10.1007/s00213-014-3612-4 · 3.88 Impact Factor
Show more