Inhibition of Glutamate Cysteine Ligase Activity Sensitizes Human Breast Cancer Cells to the Toxicity of 2-Deoxy-d-Glucose

These results show that treatment of human breast cancer cells with 2-deoxy-D-glucose causes metabolic oxidative stress that is accompanied by increases in steady-state levels of glutamate cysteine ligase mRNA, GCL activity, and glutathione content

Kelly K. Andringa

2006

Scholarcy highlights

  • Glucose metabolism has been suggested to be an integral component of the metabolic detoxification pathways, which protect tumor cells from H2O2
  • The results of the current studies showed that treatment of human breast cancer cells with 2-deoxy-D-glucose causes metabolic oxidative stress that is accompanied by increases in steadystate levels of glutamate cysteine ligase mRNA, GCL activity, and glutathione content
  • A similar analysis of the RNA levels of the modifier subunit of the GCL enzyme showed no significant increases at the 8- or 24-hour time points of 2-deoxy-D-glucose exposure. These results show that treatment of human breast cancer cells with 2-deoxy-D-glucose induced the increased expression of GCLC as well as GCL activity
  • These results provide further support for the hypothesis that GCL is a protective enzyme up-regulated in response to metabolic oxidative stress induced by exposure of human cancer cells to 2-deoxy-D-glucose
  • Cancer cells metabolize more glucose than their normal cell counterparts, and this metabolic characteristic is exploited in positron emission tomography imaging to localize cancerous tissue using F18-2-deoxy-D-glucose
  • 2-deoxy-D-glucose caused a significant increase in the GCL activity that was accompanied by increased steady-state levels of mRNA coding for GCLC. These data are consistent with the hypothesis that MDA-MB231 human breast cancer cells induce an adaptive response to treatment with 2-deoxy-D-glucose that involves the up-regulation of GSH synthesis via increased GCL activity, resulting in enhanced 2-deoxy-D-glucose resistance
  • These data are consistent with the hypothesis that MDA-MB231 human breast cancer cells induce an adaptive response to treatment with 2-deoxy-D-glucose that involves the up-regulation of GSH synthesis via increased glutamate cysteine ligase activity, resulting in enhanced 2-deoxy-D-glucose resistance

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