Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells

Kim, Ju Young; Kanai, Yoshikatsu; Chairoungdua, Arthit; Ho, Seok; Matsuo, Hirotaka; Kim, Do Kyung; Inatomi, Jun; Sawa, Hiroki; Ida, Yoshiteru; Endou, Hitoshi

doi:10.1016/s0005-2736(01)00338-8

Cited by 132 publications

(109 citation statements)

References 33 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…1 A, top blot). The density of this band was increased with xCT and Nrf2 overexpression, unlike the nonspecific band at 95 kDa, suggesting that it is derived from the xCT transcript and may be an alternatively spliced or translationally modified form distinct from 35 kDa xCT (Kim et al, 2001). No heterodimerization was observed between 4F2hc and xCT-mod.…”

Section: Characterization Of An Anti-xct Polyclonal Antibodymentioning

confidence: 87%

Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation

Shih

Erb²,

Sun³

et al. 2006

J. Neurosci.

276

254

View full text Add to dashboard Cite

The cystine/glutamate exchanger (xCT) provides intracellular cyst(e)ine for production of glutathione, a major cellular antioxidant. Using xCT overexpression and underexpression, we present evidence that xCT-dependent glutathione production modulates both neuroprotection from oxidative stress and cell proliferation. In embryonic and adult rat brain, xCT protein was enriched at the CSF-brain barrier (i.e., meninges) and also expressed in the cortex, hippocampus, striatum, and cerebellum. To examine the neuroprotective role of xCT, various non-neuronal cell types (astrocytes, meningeal cells, and peripheral fibroblasts) were cocultured with immature cortical neurons and exposed to oxidative glutamate toxicity, a model involving glutathione depletion. Cultured meningeal cells, which naturally maintain high xCT expression, were more neuroprotective than astrocytes. Selective xCT overexpression in astrocytes was sufficient to enhance glutathione synthesis/release and confer potent glutathione-dependent neuroprotection from oxidative stress. Moreover, normally nonprotective fibroblasts could be re-engineered to be neuroprotective with ectopic xCT overexpression indicating that xCT is a key step in the pathway to glutathione synthesis. Conversely, astrocytes and meningeal cells derived from sut/sut mice (xCT loss-of-function mutants) showed greatly reduced proliferation in culture attributable to increased oxidative stress and thiol deficiency, because growth could be rescued by the thiol-donor ␤-mercaptoethanol. Strikingly, sut/sut mice developed brain atrophy by early adulthood, exhibiting ventricular enlargement, thinning of the cortex, and shrinkage of the striatum. Our results indicate that xCT can provide neuroprotection by enhancing glutathione export from non-neuronal cells such as astrocytes and meningeal cells. Furthermore, xCT is critical for cell proliferation during development in vitro and possibly in vivo.

show abstract

Section: Characterization Of An Anti-xct Polyclonal Antibodymentioning

confidence: 87%

Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation

Shih

Erb²,

Sun³

et al. 2006

J. Neurosci.

276

254

View full text Add to dashboard Cite

show abstract

“…This may reflect blunted cystine-glutamate exchange because cystine uptake into the cell represents the rate-limiting step in glutathione synthesis (Bannai, 1984;Meister, 1991;Sies, 1999). Alternatively, this could cause blunted cystine-glutamate exchange because extracellular glutathione metabolism serves as a reservoir for cystine that is critical in maintaining cystine-glutamate exchange (Deneke and Fanburg, 1989;Sato et al, 1999;Sies, 1999;Kim et al, 2001;Shih et al, 2006). Regardless, either would diminish glutamate release from cystine-glutamate exchange.…”

Section: Cystine-glutamate Exchange and Schizophreniamentioning

confidence: 99%

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Baker

Madayag

Kristiansen

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by Nacetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystineglutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.

show abstract

“…Once inside the cells, cystine is rapidly reduced to cysteine, the rate-limiting substrate for glutathione (GSH) synthesis. Therefore, system xc-plays an important role in maintaining the cellular redox balance by regulating the intracellular GSH level (Sato et al, 1999(Sato et al, , 2000Kim et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

et al. 2008

View full text Add to dashboard Cite

xCT, the functional subunit of the cystine/glutamate transporter xc-system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role of xCT in tumor metastasis remains largely unknown. In this study, both xCT þ / þ and xCT À/À melanocytes were used to evaluate the role of xCT in adhesion. xCT activity was suppressed by an inhibitor, sulfasalazine (SASP), or by xCT siRNA in an esophageal cancer cell line, KYSE150. We found that disruption of xCT enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and b-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of b-catenin transcriptional activity. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation. These results first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy.

show abstract

Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells

Cited by 132 publications

References 33 publications

Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation

Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

Contact Info

Product

Resources

About