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Nat Cell Biol. 2008 May;10(5):611-8. doi: 10.1038/ncb1724. Epub 2008 Apr 6.

p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation.

Author information

1
Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, Kosugi-cho 1-396, Nakahara-ku, Kawasaki-shi, Kanagawa 211-8533, Japan.

Abstract

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-kappaB and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKKalpha and IKKbeta and subsequent NF-kappaB activity were enhanced. Activation of NF-kappaB, 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-kappaB 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-kappaB pathway through suppression of glycolysis. These results suggest that a positive-feedback loop exists, whereby glycolysis drives IKK-NF-kappaB activation, and that hyperactivation of this loop by loss of p53 is important in oncogene-induced cell transformation.

PMID:
18391940
DOI:
10.1038/ncb1724
[Indexed for MEDLINE]

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