Cells growing under reduced oxygen tension switch from aerobic to anaerobic metabolism, a considerably less efficient form in which glucose is the sole energy producing substrate through the glycolytic pathway. Since the ATP harvested from glucose in cells under hypoxia vs. those under normoxia is significantly reduced, the rate of glucose uptake and glycolysis is increased in order to meet energy demands. Central to this augmentation in glycolytic capacity is Hypoxia-Inducible Factor (HIF), which is stabilized under hypoxia and initiates the transcription of its target genes including those involving glucose uptake and glycolysis. We previously demonstrated in several reports that tumor cells growing in three distinct models of hypoxia are hypersensitive to glycolytic inhibition with the glucose analog, 2-deoxy-D-glucose (2-DG). However, HIF, through its induction of glycolytic enzymes and glucose transporters, may provide resistance to such treatment. Here using flow cytometry for analysis of cellular DNA concentration we find that a mutant cell line unable to initiate the HIF response shows a significantly higher pre-G1 phase peak (indicative of cell death) when treated with 2-DG under hypoxic conditions as compared to its wild type counterpart. Additionally, in studies where the WT and HIF-mutant cells were grown as xenografts in immuno-deficient mice we found that 2-DG treatment growth inhibited HIF-mutant tumors while WT tumors were unaffected. These findings show that induction of HIF both in vitro and in vivo provides a level of resistance to 2-DG treatment and indicate that this sugar-analog may be clinically more effective when used in conjunction with agents that inhibit HIF.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]