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
  • Source
    • "The A375 cells were selected because previous experiments related the presence of different selenium compounds — selenium nanoparticles (), selenocystine (Chen and Wong 2008), and 1,4-Diselenophene-1,4-diketone (Vinceti et al. 2014) — to oxidative stress and mitochondrial dysfunction leading to apoptosis in A375 cells. Furthermore, selenium compounds were found to be able to enhance X-ray induced growth inhibition in A375 cells (Lo et al. 2008). Using these three different cell lines, we compared cytotoxicity of selenosulfate and selenite for three different incubation times (24, 48, and 72 h) and, for HepG2 and T24 cells, in the presence and absence of NEAA as medium supplement. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Based on acute cytotoxicity studies, selenosulfate (SeSO3−) has been suggested to possess a generally higher toxic activity in tumor cells than selenite. The reason for this difference in cytotoxic activity remained unclear. In the present study, cytotoxicity tests with human hepatoma (HepG2), malignant melanoma (A375), and urinary bladder carcinoma cells (T24) showed that the selenosulfate toxicity was very similar between all three tested cell lines (IC50 6.6–7.1 μM after 24 h). It was largely independent of exposure time and presence or absence of amino acids. What changed, however, was the toxicity of selenite, which was lower than that of selenosulfate only for HepG2 cells (IC50 > 15 μM), but similar to and higher than that of selenosulfate for A375 (IC50 4.7 μM) and T24 cells (IC50 3.5 μM), respectively. Addition of amino acids to T24 cell growth medium downregulated short-term selenite uptake (1.5 versus 12.9 ng Se/106 cells) and decreased its cytotoxicity (IC50 8.4 μM), rendering it less toxic than selenosulfate. The suggested mechanism is a stronger expression of the xc− transport system in the more sensitive T24 compared to HepG2 cells which creates a reductive extracellular microenvironment and facilitates selenite uptake by reduction. Selenosulfate is already reduced and so less affected. The cytotoxic activity of selenosulfate and selenite to tumor cells therefore depends on the sensitivity of each cell line, supplements like amino acids as well as the reductive state of the extracellular environment.
    Full-text · Article · Jan 2016 · Environmental Science and Pollution Research
  • Source
    • "The availability of cysteine is related to both the glutamate/cysteine antiporter system x À c and the activity of the plasma membrane bound enzyme g-glutamyltransferase (GGT). The x À c system exchanges extracellular cysteine for intracellular glutamate thus promoting GSH synthesis [15] [16] [17]. The x À c transporter contains a specific light chain (xCT) which is also the functional subunit of the transporter. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Proteasome inhibitors may induce ER stress and oxidative stress, disrupt signaling pathways and trigger apoptosis in several cancer cells. However, they are also reported to increase glutathione (GSH) synthesis and protect cells from oxidative stress. In the present study we showed that the proteasome inhibitor lactacystin increased ROS and GSH levels after treatment of HT-29 colorectal cancer cells. The increased GSH depended upon the activity of glutamate cysteine ligase (GCL), uptake of cystine/cysteine via the cystine/glutamate transporter xc(-) and the activity of γ-glutamyltransferase (GGT). Increased transcription levels of the catalytic subunit of glutamate cysteine ligase (GCLC), the catalytic subunit xCT of xc(-) and GGT were induced by lactacystin, although with different kinetics and stoichiometry. Lactacystin treatment also augmented protein levels of GCLC, xCT and GGT but significant levels were not detected until 48 h after initiation of lactacystin treatment. These increases in protein levels were dependent on the p38 MAPK pathway. Studies in cells transfected with siRNA against the transcription factor Nrf2 demonstrated that the promoter activities of xCT and GCLC but not of GGT depended on Nrf2. However, depletion of Nrf2 had no effect on lactacystin-induced upregulation of the GGT, GCLC and xCT mRNA levels. Taken together, our results suggest that oxidative stress provoked by proteasomal inhibition results in elevation of cellular GSH levels due to increased synthesis of GSH and uptake of cystine/cysteine. Following treatment with lactacystin, enhanced expression of antioxidant components involved in GSH homeostasis is p38 MAPK-dependent, but Nrf2-independent, resulting in increased GSH synthesis capacity.
    Full-text · Article · Sep 2015 · Free Radical Research
  • 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.
    Full-text · Article · Jun 2015 · Neoplasia (New York, N.Y.)
Show more