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The FoxO–BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress

Oncogene volume 33, pages 3183–3194 (2014)Cite this article

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A Corrigendum to this article was published on 06 November 2014

Abstract

Normal cells possess adaptive mechanisms to couple energy availability with cell growth (cell size increase) and survival, and imbalances are associated with major diseases such as cancer. Inactivation of critical regulators involved in energy stress response, including adenosine monophosphate-activated protein kinase (AMPK), liver kinase B1 (LKB1), tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to uncontrolled cell growth yet increased apoptosis under energy stress. These energy stress regulators are also important in tumor suppression and metabolism. Here, we show that forkhead box O (FoxO) transcription factor, a central regulator of tumor suppression and metabolism, plays a unique role in energy stress response. FoxOs inhibit the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell growth, under energy stress, and inactivation of FoxOs alleviates energy stress-mediated mTORC1 repression. Surprisingly, unlike AMPK-, Lkb1- or Tsc1/2-deficient cells, FoxO-deficient cells exhibit decreased apoptosis under energy stress. FoxOs operate to inhibit mTORC1 signaling and cell survival independent of AMPK and TSC. Integrated transcriptomic and functional analyses identified BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)—a negative regulator of both Rheb and Bcl2 prosurvival family members—as a key downstream target of FoxOs to inhibit mTORC1 function and promote apoptosis in response to energy stress. We show that p38β, but not AMPK, is likely to function upstream of FoxO–BNIP3 to mediate energy stress response. Finally, we reveal that low expression of FoxO or BNIP3 correlates with poor clinical outcomes in renal cancer patients. Together, our study uncovers a novel signaling circuit functioning to mediate cellular energy responses to control cell growth and survival. These findings also have important implications to human cancers.

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Acknowledgements

We thank Drs Junjie Chen and Hui-Kuan Lin for critical reading of the paper. We also thank Dr Benoit Viollet for providing AMPK WT and KO MEFs and Dr Hsiao-Sheng Liu for providing BNIP3 expression plasmid. BG would also like to thank Ron DePinho for his encouragement and suggestions on this study. This study has been supported by grants from MD Anderson Cancer Center, US Department of Defense (TS093049 and PC100356), LAM Foundation (LAM092P01-12), Concern Foundation and Sidney Kimmel Foundation (to BG) and the TCGA grant U24CA143883 from NCI/NIH (to JY). BG is a Kimmel Scholar and a member of the MD Anderson Cancer Center (CA016672).

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  1. TCGA Genome Data Analysis Center, The University of Texas MD Anderson Cancer Center, The University of Texas—Houston Health Science Center, Houston, TX, USA

Authors and Affiliations

  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Lin, L Zhuang, D Wang & B Gan

  2. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Yao

  3. Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China

    J Han

  4. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK

    E W-F Lam

  5. Program of Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    B Gan

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Lin, A., Yao, J., Zhuang, L. et al. The FoxO–BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress. Oncogene 33, 3183–3194 (2014). https://doi.org/10.1038/onc.2013.273

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