Glutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathionine-gamma-lyase and upregulation of the transsulfuration pathway in C6 glioma cells
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|Title:||Glutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathionine-gamma-lyase and upregulation of the transsulfuration pathway in C6 glioma cells||Authors:||Kandil, Sarah
McBean, Gethin J.
|Permanent link:||http://hdl.handle.net/10197/6620||Date:||Mar-2010||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 View the MathML source 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 View the MathML source exchanger with the gliotoxins l-αaminoadipate or l-β-N-oxalylamino-l-alanine (400 μM) caused a loss of cellular cysteine and depletion in glutathione to 51% and 54% of control, respectively, after 24 h. Inhibition of the transsulfuration pathway with propargylglycine (1 mM, 24 h) depleted glutathione to 77% of control. Co-incubation of cells with gliotoxin and propargylglycine reduced glutathione to 39% of control at 24 h and to 20% at 48 h. 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 3 h 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.||Funding Details:||Science Foundation Ireland||Type of material:||Journal Article||Publisher:||Elsevier||Copyright (published version):||2010 Elsevier||Keywords:||Cystine-glutamate exchanger;Gliotoxin;Astrocyte;Transulfuration;C6 glioma;Cystathionine-g-lyase;Glutathione||DOI:||10.1016/j.neuint.2010.01.004||Language:||en||Status of Item:||Peer reviewed|
|Appears in Collections:||Biomolecular and Biomedical Science Research Collection|
Agriculture and Food Science Research Collection
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