Type

Journal Article

Authors

Gethin J. McBean
Lorraine Brennan
Sarah Kandil

Subjects

Biochemistry

Topics
glutathione astrocyte gliotoxin cystine glutamate exchanger c6 glioma cystathionine g lyase transulfuration cystathionine gamma lyase

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 (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.
Collections Ireland -> University College Dublin -> Biomolecular and Biomedical Science Research Collection
Ireland -> University College Dublin -> College of Agriculture, Food Science and Veterinary Medicine (superseded in 2015)
Ireland -> University College Dublin -> Agriculture and Food Science Research Collection (superseded in 2015)
Ireland -> University College Dublin -> College of Science
Ireland -> University College Dublin -> School of Agriculture and Food Science (superseded in 2015)
Ireland -> University College Dublin -> School of Biomolecular & Biomedical Science

Full list of authors on original publication

Gethin J. McBean, Lorraine Brennan, Sarah Kandil

Experts in our system

1
Gethin J. McBean
University College Dublin
Total Publications: 32
 
2
Lorraine Brennan
University College Dublin
Total Publications: 166