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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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References

  1. Folkman, J. Angiogenesis and apoptosis. Semin. Cancer Biol. 13, 159–167 (2003)

    Article  CAS  Google Scholar 

  2. Jones, R. G. & Thompson, C. B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 23, 537–548 (2009)

    Article  CAS  Google Scholar 

  3. Shackelford, D. B. & Shaw, R. J. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer 9, 563–575 (2009)

    Article  CAS  Google Scholar 

  4. Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002)

    Article  CAS  ADS  Google Scholar 

  5. Kato, K. et al. Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene 21, 6082–6090 (2002)

    Article  CAS  Google Scholar 

  6. Laderoute, K. R. et al. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol. Cell. Biol. 26, 5336–5347 (2006)

    Article  CAS  Google Scholar 

  7. Chhipa, R. R., Wu, Y., Mohler, J. L. & Ip, C. Survival advantage of AMPK activation to androgen-independent prostate cancer cells during energy stress. Cell. Signal. 22, 1554–1561 (2010)

    Article  CAS  Google Scholar 

  8. Corradetti, M. N., Inoki, K., Bardeesy, N., DePinho, R. A. & Guan, K. L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz–Jeghers syndrome. Genes Dev. 18, 1533–1538 10.1101/gad.1199104. (2004)

  9. Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004)

    Article  CAS  ADS  Google Scholar 

  10. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005)

    Article  CAS  Google Scholar 

  11. Le Goffe, C. et al. Metabolic control of resistance of human epithelial cells to H2O2 and NO stresses. Biochem. J. 364, 349–359 (2002)

    Article  CAS  Google Scholar 

  12. Hardie, D. G. & Pan, D. A. Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase. Biochem. Soc. Trans. 30, 1064–1070 (2002)

    Article  CAS  Google Scholar 

  13. Abu-Elheiga, L., Matzuk, M. M., Abo-Hashema, K. A. & Wakil, S. J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291, 2613–2616 (2001)

    Article  CAS  ADS  Google Scholar 

  14. Zhou, W. et al. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 63, 7330–7337 (2003)

    CAS  PubMed  Google Scholar 

  15. Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009)

    Article  CAS  ADS  Google Scholar 

  16. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009)

    Article  CAS  ADS  Google Scholar 

  17. Jang, T. et al. 5′-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat. Int. J. Cancer 128, 2230–2239 (2011)

    Article  CAS  Google Scholar 

  18. Kim, H. S. et al. Microarray analysis of papillary thyroid cancers in Korean. Korean J. Intern. Med. 25, 399–407 (2010)

    Article  CAS  Google Scholar 

  19. Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011)

    Article  CAS  Google Scholar 

  20. Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005)

    Article  CAS  Google Scholar 

  21. Migita, T. et al. Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J. Natl. Cancer Inst. 101, 519–532 (2009)

    Article  CAS  Google Scholar 

  22. Knowles, L. M., Yang, C., Osterman, A. & Smith, J. W. Inhibition of fatty-acid synthase induces caspase-8-mediated tumor cell apoptosis by up-regulating DDIT4. J. Biol. Chem. 283, 31378–31384 (2008)

    Article  CAS  Google Scholar 

  23. Bandyopadhyay, S. et al. Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res. 66, 5934–5940 (2006)

    Article  CAS  Google Scholar 

  24. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009)

    Article  CAS  ADS  Google Scholar 

  25. Migita, T. et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 68, 8547–8554 (2008)

    Article  CAS  Google Scholar 

  26. Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007)

    Article  CAS  ADS  Google Scholar 

  27. Bhaskar, P. T. et al. mTORC1 hyperactivity inhibits serum deprivation-induced apoptosis via increased hexokinase II and GLUT1 expression, sustained Mcl-1 expression, and glycogen synthase kinase 3β inhibition. Mol. Cell. Biol. 29, 5136–5147 (2009)

    Article  CAS  Google Scholar 

  28. Li, D. et al. A new G6PD knockdown tumor-cell line with reduced proliferation and increased susceptibility to oxidative stress. Cancer Biother. Radiopharm. 24, 81–90 (2009)

    Article  CAS  Google Scholar 

  29. Budanov, A. V. & Karin, M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 10.1016/j.cell.2008.06.028. (2008)

  30. Skeen, J. E. et al. Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell 10, 269–280 (2006)

    Article  CAS  Google Scholar 

  31. Kennedy, S. G. et al. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11, 701–713 (1997)

    Article  CAS  Google Scholar 

  32. Wagner, T. C. & Scott, M. D. Single extraction method for the spectrophotometric quantification of oxidized and reduced pyridine nucleotides in erythrocytes. Anal. Biochem. 222, 417–426 (1994)

    Article  CAS  Google Scholar 

  33. Zerez, C. R., Lee, S. J. & Tanaka, K. R. Spectrophotometric determination of oxidized and reduced pyridine nucleotides in erythrocytes using a single extraction procedure. Anal. Biochem. 164, 367–373 (1987)

    Article  CAS  Google Scholar 

  34. Rahman, I., Kode, A. & Biswas, S. K. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nature Protocols 1, 3159–3165 (2006)

    Article  CAS  Google Scholar 

  35. Buzzai, M. et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene 24, 4165–4173 (2005)

    Article  CAS  Google Scholar 

  36. Deberardinis, R. J., Lum, J. J. & Thompson, C. B. Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J. Biol. Chem. 281, 37372–37380 (2006)

    Article  CAS  Google Scholar 

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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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