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Glutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathionine-γ-lyase and upregulation of the transsulfuration pathway in C6 glioma cells
- Source :
-
Neurochemistry International . Mar2010, Vol. 56 Issue 4, p611-619. 9p. - Publication Year :
- 2010
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Abstract
- Abstract: Cancer cells have a high demand for cysteine as precursor of the antioxidant, glutathione, that is required to promote cell growth and division. Uptake of cystine by the cystine-glutamate exchanger provides the majority of cysteine, but a significant percentage may be derived from methionine, via a transsulfuration pathway. Our aim was to evaluate the relative contribution of the exchanger and the transsulfuration pathway to glutathione synthesis in astrocytoma/glioblastoma cells, using the C6 glioma cell line as a model system. Blockade of the exchanger with the gliotoxins l-αaminoadipate or l-β-N-oxalylamino-l-alanine (400μM) caused a loss of cellular cysteine and depletion in glutathione to 51% and 54% of control, respectively, after 24h. Inhibition of the transsulfuration pathway with propargylglycine (1mM, 24h) depleted glutathione to 77% of control. Co-incubation of cells with gliotoxin and propargylglycine reduced glutathione to 39% of control at 24h and to 20% at 48h. Expression of cystathionine-γ-lyase, the rate-limiting enzyme of the transsulfuration pathway, was significantly increased following incubation of the cells with gliotoxins. Incubation of C6 cells with diethylmaleate for 3h led to a significant reduction in glutathione (63%), whereas expression of cystathionine-γ-lyase was increased by 1.5-fold. Re-feeding methionine to diethylmaleate-treated cells incubated in the absence of cystine or methionine resulted in a significant recovery in glutathione that was blocked by propargylglycine. Co-incubation of C6 cells with diethylmaleate and the JNK-inhibitor, SP600125, abolished the increase in expression of cystathionine-γ-lyase that had been observed in the presence of diethylmaleate alone. Similar results were obtained with the p38MAPK inhibitor, SB203580. It is concluded that glutathione depletion causes a JNK- and p38MAPK-mediated increase in expression of cystathionine-γ-lyase that promotes flux through the transsulfuration pathway to compensate for loss of glutathione in C6 glioma cells. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 01970186
- Volume :
- 56
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Neurochemistry International
- Publication Type :
- Academic Journal
- Accession number :
- 48400547
- Full Text :
- https://doi.org/10.1016/j.neuint.2010.01.004