P53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation

Cancer cells use aerobic glycolysis preferentially for energy provision(1,2) and this metabolic change is important for tumour growth(3,4). Here, we have found a link between the tumour suppressor p53, the transcription factor NF-kappa B and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKK alpha and IKK beta and subsequent NF-kappa B activity were enhanced. Activation of NF-kappa B, by loss of p53, caused an increase in the rate of aerobic glycolysis and upregulation of Glut3. Oncogenic Ras-induced cell transformation and acceleration of aerobic glycolysis in p53-deficient cells were suppressed in the absence of p65/ NF-kappa B expression, and were restored by GLUT3 expression. It was also shown that a glycolytic inhibitor diminished the enhanced IKK activity in p53-deficient cells. Moreover, in Ras-expressing p53-deficient cells, IKK activity was suppressed by p65 deficiency and restored by GLUT3 expression. Taken together, these data indicate that p53 restricts activation of the IKK - NF-kappa B pathway through suppression of glycolysis. These results suggest that a positivefeedback loop exists, whereby glycolysis drives IKK - NF-kappa B activation, and that hyperactivation of this loop by loss of p53 is important in oncogene- induced cell transformation.