Abstract
Cancer cells use aerobic glycolysis preferentially for energy provision1,2 and this metabolic change is important for tumour growth3,4. Here, we have found a link between the tumour suppressor p53, the transcription factor NF-κB and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKKα and IKKβ and subsequent NF-κB activity were enhanced. Activation of NF-κB, 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-κB 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-κB pathway through suppression of glycolysis. These results suggest that a positive-feedback loop exists, whereby glycolysis drives IKK–NF-κB activation, and that hyperactivation of this loop by loss of p53 is important in oncogene-induced cell transformation.
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Acknowledgements
We thank T. Taniguchi, M. Oren, H. Hirata, K. Sada, S. Minami, S. Ohta, S. Asoh, O. Kawanami, I. Ohsawa, W. A. Martin, E. Oda-Sato, Y. Abe, W. Nakajima and M. Ando for discussion; T. Doi, S. Mise and Y. Asano for technical support; I. Uehara for preparation of MEFs; R. Agami for the retroviral vectors pSuper-sh human p53 puro; D. V. Goeddel for IKKα and IKKβ cDNA. This work was supported by Grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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K. K. and N. T. designed the study; K. K., with contributions from K. A. and K. T., performed all experiments; K. K. and N. T. wrote the manuscript.
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Kawauchi, K., Araki, K., Tobiume, K. et al. p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nat Cell Biol 10, 611–618 (2008). https://doi.org/10.1038/ncb1724
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DOI: https://doi.org/10.1038/ncb1724
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