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McBean, Gethin J.
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McBean, Gethin J.
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McBean, Gethin J.
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- PublicationThe thiol redox system in glioma biology : clinical target and significance in resistance to glioma chemotherapySulfur-containing compounds play an essential role in maintaining redox balance in glioma cells. Chief amongst these are the reduced and oxidised (disulfide) forms of cysteine (cysteine/cystine) and glutathione (GSH /GSSG) as well as thioredoxin and glutaredoxin, members of the thiol-disulfide oxidoreductases. GSH is also important as an antioxidant, as a ‘safe’ storage form of cysteine and for detoxification reactions involving the GSH sulfur transferase family of enzymes. Glioma cells contain a high concentration of GSH, compared to normal astrocytes, which renders these cells particularly resistant to chemotherapeutic agents. The rate of synthesis of GSH is controlled by the availability of cysteine, which is imported in its oxidised form, cystine, through specialized channels in the plasma membrane. These channels, known as the cystine-glutamate xc- exchanger, operate by taking up cystine in exchange for glutamate, which is released into the extracellular medium. Glioma cells export large quantities of glutamate by this mechanism, which, if unchecked, causes damage and eventual death of surrounding neurones. Thus, GSH synthesis in glioma cells fuels resistance to chemotherapy and, at the same time, kills off surrounding neurones thereby providing space for tumor cell growth. Much is now known of the molecular mechanism of cystine import and of GSH synthesis in glioma cells. In particular, a number of therapeutic strategies that target the cystine-glutamate exchanger have been proposed on the basis that this would inhibit synthesis of GSH and remove the source of glutamate release. This review describes new developments in the field of glioma cell redox balance and evaluates the potential for clinical intervention at the level of cysteine and GSH biosynthesis that may prove effective in combating brain tumor growth and development.
303 - PublicationThe transsulfuration pathway : a source of cysteine for glutathione in astrocytesAstrocyte cells require cysteine as a substrate for glutamate cysteine ligase (γ-glutamylcysteine synthase; EC 6.3.2.2) catalyst of the rate-limiting step of the γ-glutamylcycle leading to formation of glutathione (l-γ-glutamyl-l-cysteinyl-glycine; GSH). In both astrocytes and glioblastoma/astrocytoma cells, the majority of cysteine originates from reduction of cystine imported by the x c − cystine-glutamate exchanger. However, the transsulfuration pathway, which supplies cysteine from the indispensable amino acid, methionine, has recently been identified as a significant contributor to GSH synthesis in astrocytes. The purpose of this review is to evaluate the importance of the transsulfuration pathway in these cells, particularly in the context of a reserve pathway that channels methionine towards cysteine when the demand for glutathione is high, or under conditions in which the supply of cystine by the x c − exchanger may be compromised.
1211Scopus© Citations 175 - PublicationGlutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathionine-gamma-lyase and upregulation of the transsulfuration pathway in C6 glioma cellsCancer 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.
431Scopus© Citations 47