p53 regulates glucose metabolism through an IKK-NF-?B pathway and inhibits cell transformation
Cancer cells use aerobic glycolysis preferentially for energy provision and this metabolic change is important for tumour growth. Here, we have found a link between the tumour suppressor p53, the transcription factor NF-?B and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKK? and IKK? and subsequent NF-?B activity were enhanced. Activation of NF-?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-?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-?B pathway through suppression of glycolysis. These results suggest that a positive-feedback loop exists, whereby glycolysis drives IKK?NF-?B activation, and that hyperactivation of this loop by loss of p53 is important in oncogene-induced cell transformation.
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