A UNIQUE GLUCOSE-DEPENDENT APOPTOTIC PATHWAY INDUCED BY C-MYC

The lactate dehydrogenase A (LDH-A) gene, whose product participates i n normal anaerobic glycolysis and is frequently increased in human can cers, has been identified as a c-Myc-responsive gene, It was of intere st, therefore, to compare the effect of glucose deprivation in c-Myc-t ransformed and nontransformed cells, We observed that glucose deprivat ion or treatment with the glucose antimetabolite 2-deoxyglucose caused nontransformed cells to arrest in the G(0)/G(1) phase of the cell cyc le, In contrast, c-Myc-transformed fibroblasts, lymphoblastoid, or lun g carcinoma cells underwent extensive apoptosis, Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis w ith glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis i s blocked, The apoptosis caused by glucose deprivation was blocked by Bcl-2 expression but appeared to be independent of wild-type p53 activ ity. These studies provide insights on the coupling of glucose metabol ism and the cell cycle in c-Myc-transformed cells and may in the futur e be exploited for cancer therapeutics.