Genotoxic exposure is associated with alterations in glucose uptake and metabolism

Recent observations suggest that growth factor withdrawal can promote cell death in part through modulation of basic cellular bioenergetic pathways, including inhibition of glucose uptake and glycolytic metabolism. Whether DNA damage-initiated cell death pathways also involve bioenergetic deregulation has not been studied previously. Subtractive suppressive hybridization was used to identify changes in gene expression in murine cells after exposure to genotoxic stimuli, including cisplatin, etoposide, and gamma-radiation. Among the genes identified in this screen were several that regulate glycolytic metabolism. Enzymes that catalyze key regulatory steps of glycolysis, including hexokinase, phosphofructokinase, and pyruvate kinase, appeared to be coordinately down-regulated by genotoxic exposure. Northern blotting confirmed that these changes in gene expression occur within 4 h of exposure to several DNA-damaging agents. Genotoxic exposure was found to similarly inhibit expression of both glut-1 and glut-3, genes that encode critical regulators of glucose uptake. Direct measurement of glycolytic rate and of oxygen consumption confirmed that genotoxic exposure resulted in suppression of both anaerobic and aerobic metabolism. Many of these metabolic changes mimic those observed after growth factor withdrawal. Together, these observations suggest that multiple apoptotic triggers, including growth factor withdrawal and genotoxic exposure, suppress cellular bioenergetic pathways. Mitochondrial responses to the resulting rapid decrease in metabolic substrates may play an important role in initiation of apoptotic cell death.