A mechanism for glutamate toxicity in the C6 glioma cells involving inhibition of cystine uptake leading to glutathione depletion

Kato, Satoru; Negishi, K.; Mawatari, Kazuhiro; Kuo, Che‐Hui

doi:10.1016/0306-4522(92)90278-a

Cited by 133 publications

(78 citation statements)

References 36 publications

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“…Although poorly understood at present, these attributes suggest a dynamic role for the heterodimers in linking solute transport to proliferation-related aspects of the immediate cellular environment. Correlative studies have indicated that GSH levels are linked to cystine transport in a number of cells including endothelial cells [35,55], smooth muscle cells [56], macrophages [57], fibroblasts [58], brain cells [40,59] and pancreatic acinar and islet cells [60]. Although xCT is generally thought to impact chemotherapeutic resistance [33,37], our results show that it directly impacts cell proliferation signaling through AP-1 by increasing GSH levels in mouse fibroblasts.…”

Section: Discussionmentioning

confidence: 66%

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xCT expression reduces the early cell cycle requirement for calcium signaling

Lastro

Kourtidis

Farley

et al. 2008

Cellular Signalling

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Calcium has long been recognized as an important regulator of cell cycle transitions although the mechanisms are largely unknown. A functional genomic screen has identified genes involved in the regulation of early cell cycle progression by calcium. These genes when overexpressed confer the ability to bypass the G1/S arrest induced by Ca 2+ -channel antagonists in mouse fibroblasts. Overexpression of the cystine-glutamate exchanger, xCT, had the greatest ability to evade calcium antagonist-induced cell cycle arrest. xCT carries out the rate limiting step of glutathione synthesis in many cell types and is responsible for the uptake of cystine in most human cancer cell lines. Functional analysis indicates that the cystine uptake activity of xCT overcomes the G1/S arrest induced by Ca 2+ -channel antagonists by bypassing the requirement for calcium signaling. Since cells overexpressing xCT were found to have increased levels and activity of the AP-1 transcription factor in G1, redox stimulation of AP-1 activity accounts for the observed growth of these cells in the presence of calcium channel antagonists. These results suggest that reduced calcium signaling impairs AP-1 activation and that xCT expression may directly affect cell proliferation.

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Section: Discussionmentioning

confidence: 66%

“…Growth factor (PDGF)-induced cell cycle progression results from activation of the Ras/Mek/ Erk MAPk and the PI3kinase/AKT pathways which are involved in accumulation and stabilization of cyclin D1 proteins and in the elimination of the cell cycle inhibitor, p27 [40]. .…”

Section: Cells Overexpressing Xct Exhibit Increased Ap-1 Activitymentioning

confidence: 99%

xCT expression reduces the early cell cycle requirement for calcium signaling

Lastro

Kourtidis

Farley

et al. 2008

Cellular Signalling

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“…High glutamate levels block cystine uptake via the amino acid transporter Xc Ϫ and impairs reduced glutathione (GSH) cell homeostasis. The induction of oxidative stress by glutamate in this model has been demonstrated to be a primary cytotoxic mechanism in C6 glial cells (23,24), PC-12 neuronal cells (25,26), immature cortical neurons cells (22), and oligodendroglia cells (27). Recently, the mitochondrial electron transport chain has been shown to be a source of ROS production during glutamate-induced apoptosis in HT22 neuronal cells, a sub-clone of HT4 cells used in the current study (21).…”

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confidence: 75%

Molecular Basis of Vitamin E Action

Sen

Khanna

Roy

et al. 2000

Journal of Biological Chemistry

279

113

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HT4 hippocampal neuronal cells were studied to compare the efficacy of tocopherols and tocotrienol to protect against glutamate-induced death. Tocotrienols were more effective than ␣-tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of ␣-tocopherol. Vitamin E molecules have potent antioxidant properties. Results show that at low concentrations, tocotrienols may have protected cells by an antioxidant-independent mechanism. Examination of signal transduction pathways revealed that protein tyrosine phosphorylation processes played a central role in the execution of death. Activation of pp60 c-Src kinase and phosphorylation of ERK were observed in response to glutamate treatment. Nanomolar amounts of ␣-tocotrienol, but not ␣-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase. Overexpression of kinase-active cSrc sensitized cells to glutamate-induced death. Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. ␣-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains. This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4 -10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.

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“…This form of inducible neuronal death is referred to as oxytosis (18 -20). The induction of oxidative stress by glutamate in this model has been demonstrated to be a primary cytotoxic mechanism in C6 glial cells (21)(22)(23), PC-12 neuronal cells (24,25), immature cortical neurons cells (17), and oligodendoglial cells (26).…”

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confidence: 76%

Molecular Basis of Vitamin E Action

Khanna

Roy

Ryu

et al. 2003

Journal of Biological Chemistry

261

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Vitamin E is a generic term for tocopherols and tocotrienols. This work is based on our striking evidence that, in neuronal cells, nanomolar concentrations of ␣-tocotrienol, but not ␣-tocopherol, block glutamate-induced death by suppressing early activation of c-Src kinase (Sen, C. K., Khanna, S., Roy, S., and Packer, L. (2000) J. Biol. Chem. 275, 13049 -13055). This study on HT4 and immature primary cortical neurons suggests a central role of 12-lipoxygenase (12-LOX) in executing glutamate-induced neurodegeneration. BL15, an inhibitor of 12-LOX, prevented glutamate-induced neurotoxicity. Moreover, neurons isolated from 12-LOX-deficient mice were observed to be resistant to glutamate-induced death. In the presence of nanomolar ␣-tocotrienol, neurons were resistant to glutamate-, homocysteine-, and L-buthionine sulfoximine-induced toxicity. Long-term time-lapse imaging studies revealed that neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility was arrested in response to glutamate challenge. Tocotrienol-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate. The study of 12-LOX activity and metabolism revealed that this key mediator of glutamate-induced neurodegeneration is subject to control by the nutrient ␣-tocotrienol. In silico docking studies indicated that ␣-tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. These findings lend further support to ␣-tocotrienol as a potent neuroprotective form of vitamin E.

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A mechanism for glutamate toxicity in the C6 glioma cells involving inhibition of cystine uptake leading to glutathione depletion

Cited by 133 publications

References 36 publications

xCT expression reduces the early cell cycle requirement for calcium signaling

xCT expression reduces the early cell cycle requirement for calcium signaling

Molecular Basis of Vitamin E Action

Molecular Basis of Vitamin E Action

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