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

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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Figure 1: The failure to activate AMPK accelerates NADPH depletion, oxidative stress and cell death in the absence of glucose.
Figure 2: ACC2 ablation recapitulates AMPK activation, maintaining the NADPH level and decreasing the H 2 O 2 level during glucose deprivation.
Figure 3: AMPK-mediated inhibition of ACC1 is required to maintain the NADPH and reactive oxygen species levels after matrix detachment.
Figure 4: AMPK-mediated inhibition of ACC1 or ACC2 promotes 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.).

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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.

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Correspondence to Nissim Hay.

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The authors declare no competing financial interests.

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Jeon, SM., Chandel, N. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012). https://doi.org/10.1038/nature11066

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