Differentiation of substrate and non-substrate inhibitors of transport system xc−: an obligate exchanger of L-glutamate and L-cystine

Patel, Sarjubhai A.; Warren, Brady A.; Rhoderick, Joseph F.; Bridges, Richard J.

doi:10.1016/j.neuropharm.2003.08.006

Cited by 139 publications

(171 citation statements)

References 42 publications

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“…Subsequently, we analyzed the effects of (S)-4CPG, a competitive small molecule inhibitor targeting system X c À activity and thus glutamate release Patel et al, 2004;Savaskan et al, 2008). As suggested, the ability of (S)-4CPG to reduce F98 glioma cell growth (using medium containing 10% FCS) is essentially dependent on the concentrations of extracellular cystine (Figure 3a).…”

Section: Resultsmentioning

confidence: 92%

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

et al. 2010

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Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system X c À , a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system X c À activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumorimplanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system X c À activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for rapid proliferation.

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Section: Resultsmentioning

confidence: 92%

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

et al. 2010

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“…Furthermore, the role of xCT has been difficult to conclusively study because its antagonist pharmacology can overlap with glutamate receptors (Patel et al, 2004). Here, we tested the hypothesis that enhanced xCT activity is sufficient to confer neuroprotection by promoting GSH synthesis and delivery from non-neuronal support cells (astrocytes and meningeal cells) to immature neurons.…”

Section: Introductionmentioning

confidence: 99%

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

Shih

Erb²,

Sun³

et al. 2006

J. Neurosci.

276

254

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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.

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“…3 It is thus likely that occurrence of cystathionine in the immune tissues is dependent on the transport activity of system x c Ϫ . Patel et al (29) have analyzed the differences of substrate and non-substrate inhibitors of system x c Ϫ and revealed that potent inhibitors such as L-quisqualate and (S)-4-carboxyphenylglycine were not always substrates for system x c Ϫ . They also showed that cystathionine significantly inhibits the activity of glutamate uptake, although it has remained unclear whether it is a direct substrate for system x c Ϫ .…”

Section: Discussionmentioning

confidence: 99%

Cystathionine Is a Novel Substrate of Cystine/Glutamate Transporter

Kobayashi

Sato

Kasakoshi

et al. 2015

Journal of Biological Chemistry

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Differentiation of substrate and non-substrate inhibitors of transport system xc−: an obligate exchanger of L-glutamate and L-cystine

Cited by 139 publications

References 42 publications

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

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

Cystathionine Is a Novel Substrate of Cystine/Glutamate Transporter

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