Letter | Published:

AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress

Nature volume 485, pages 661665 (31 May 2012) | Download Citation

Abstract

Overcoming metabolic stress is a critical step for solid tumour growth1,2. However, the underlying mechanisms of cell death and survival under metabolic stress are not well understood. A key signalling pathway involved in metabolic adaptation is the liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK) pathway2,3. Energy stress conditions that decrease intracellular ATP levels below a certain level promote AMPK activation by LKB1. Previous studies showed that LKB1-deficient or AMPK-deficient cells are resistant to oncogenic transformation and tumorigenesis4,5,6, possibly because of the function of AMPK in metabolic adaptation. However, the mechanisms by which AMPK promotes metabolic adaptation in tumour cells are not fully understood. Here we show that AMPK activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 and ACC2 by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty-acid synthesis and increasing NADPH generation by means of fatty-acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumour formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth and solid tumour formation in vivo.

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Acknowledgements

We thank B. Viollet for the AMPK-KO MEFs, M. R. Montminy for the ACC complementary DNA, and G. Hatzivassiliou for comments on the manuscript. This work was supported by grants CA090764, AG016927 and AG025953 from the National Institutes of Health, by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community, and by grant P60DK20595 to the Diabetes Research and Training Center, University of Chicago (to N.H.).

Author information

Author notes

    • Sang-Min Jeon

    Present address: Research Oncology, Genentech, South San Francisco, California 94080, USA

Affiliations

  1. Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607, USA

    • Sang-Min Jeon
    •  & Nissim Hay
  2. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA

    • Navdeep S. Chandel

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Contributions

S.-M.J. and N.H. designed the experiments. S.-M.J. performed the experiments. N.S.C. provided advice. S.-M.J. and N.H. analysed the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nissim Hay.

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DOI

https://doi.org/10.1038/nature11066

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