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A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence

Nature volume 498, pages 109–112 (2013)Cite this article

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Abstract

In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer1,2,3,4,5. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players6. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells7,8,9,10, and senescent cells are thought to remain metabolically active11, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAFV600E, an oncogene commonly mutated in melanoma and other cancers. BRAFV600E-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAFV600E-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically.

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Figure 1: The PDK1–PDP2–PDH axis is deregulated in OIS.
Figure 2: PDP2 regulates metabolic rewiring and OIS.
Figure 3: PDK1 regulates metabolic rewiring and OIS, and acts tumorigenically.
Figure 4: PDK1 depletion causes melanoma regression and eradicates subpopulations resistant to targeted BRAFV600E inhibition.

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Acknowledgements

We thank J.-Y. Song for pathological analysis, M. McMahon for providing BrafCA mice, C. Vogel for sharing cell lines, R. van Amerongen for critical reading of the manuscript, and all members of the Gottlieb and Peeper laboratories for their input. This work was supported by Cancer Research UK, Spanish Government-EU-FEDER (grants SAF2011-25726 and ISCIII-RTICC-RD6/0020/0046) and ICREA-Academia to M.C., Israel Cancer Research Foundation and Israel Science Foundation to T.S., a Vici grant from the Netherlands Organization for Scientific Research (NWO) and a Queen Wilhelmina Award grant from the Dutch Cancer Society (KWF Kankerbestrijding) to D.S.P.

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Author notes

  1. Liang Zheng and Katrin Meissl: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands,

    Joanna Kaplon, Katrin Meissl & Daniel S. Peeper

  2. Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK,

    Liang Zheng, Barbara Chaneton, Gillian Mackay & Eyal Gottlieb

  3. Department of Biochemistry and Molecular Biology and IBUB, Faculty of Biology, Universitat de Barcelona, Av Diagonal 643, 08028 Barcelona, Spain,

    Vitaly A. Selivanov & Marta Cascante

  4. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036 Barcelona, Spain,

    Vitaly A. Selivanov & Marta Cascante

  5. Department of Clinical Oncology, Experimental Cancer Immunology and Therapy, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands,

    Sjoerd H. van der Burg & Elizabeth M. E. Verdegaal

  6. Computer Science Department, Technion, Israel Institute of Technology, Haifa 32000, Israel,

    Tomer Shlomi

  7. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, 08544, New Jersery, USA

    Tomer Shlomi

Authors
  1. Joanna Kaplon
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Contributions

J.K., E.G. and D.S.P. conceived the project, analysed the data and wrote the manuscript. J.K. performed all in vitro experiments and carried out the in vivo experiments together with K.M. J.K., K.M. and B.C. performed metabolic experiments. L.Z. and G.M. performed LC–MS analyses. S.H.B. and E.M.E.V. provided low passage melanoma cell lines. V.A.S., M.C. and T.S. helped with metabolic analyses. All authors discussed the results and commented on the manuscript. E.G. and D.S.P. contributed equally to this work.

Corresponding authors

Correspondence to Eyal Gottlieb or Daniel S. Peeper.

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Competing interests

A patent application for combined PDK and MAPK/ERK pathway inhibition in neoplasia has been filed, with J.K. and D.S.P. as inventors.

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Kaplon, J., Zheng, L., Meissl, K. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013). https://doi.org/10.1038/nature12154

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