Deregulated MYC expression induces dependence upon AMPK-related kinase 5 (original) (raw)

Nature volume 483, pages 608–612 (2012)Cite this article

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Abstract

Deregulated expression of the MYC oncoprotein contributes to the genesis of many human tumours, yet strategies to exploit this for a rational tumour therapy are scarce. MYC promotes cell growth and proliferation, and alters cellular metabolism to enhance the provision of precursors for phospholipids and cellular macromolecules1,2. Here we show in human and murine cell lines that oncogenic levels of MYC establish a dependence on AMPK-related kinase 5 (ARK5; also known as NUAK1) for maintaining metabolic homeostasis and for cell survival. ARK5 is an upstream regulator of AMPK and limits protein synthesis via inhibition of the mammalian target of rapamycin 1 (mTORC1) signalling pathway. ARK5 also maintains expression of mitochondrial respiratory chain complexes and respiratory capacity, which is required for efficient glutamine metabolism. Inhibition of ARK5 leads to a collapse of cellular ATP levels in cells expressing deregulated MYC, inducing multiple pro-apoptotic responses as a secondary consequence. Depletion of ARK5 prolongs survival in MYC-driven mouse models of hepatocellular carcinoma, demonstrating that targeting cellular energy homeostasis is a valid therapeutic strategy to eliminate tumour cells that express deregulated MYC.

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Data deposits

Array results have been deposited in ArrayExpress (http://www.ebi.ac.uk/arrayexpress/) under accession number E-MEXP-3543.

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Acknowledgements

We thank R. Baumann for immunohistochemical staining, B. Samans, A. Filmer and M. Krause for help with the siRNA screen and expression array analysis, A. Rath for help with analysis of human tumour samples, W. Kolch for siRNA targeting LATS1, S. Lowe and J. Zuber for providing the tTGMP vector, S. Martin for His-tagged annexin V expression vector, P. Schirmacher for human HCC cell lines, V. Ellenrieder for human pancreatic cancer cell lines, H. Riedesel and the staff of the Helmholtz Centre for Infection Research animal facility for technical assistance. We thank P. Gallant and all members of the Eilers laboratory for critical reading of the manuscript. Funding for this work was provided by the GROWTHSTOP consortium of the European Union, the Deutsche Forschungsgemeinschaft via the Transregio 17 (M.E.), the Transregio 77 (L.Z.) and the Emmy Noether Programme ZE 545/2-1 (L.Z.), the Bundesministerium für Bildung und Forschung, the Senate of Berlin, the University of Wuerzburg Graduate School of Life Sciences and the “Rebirth” Cluster of Excellence.

Author information

Author notes

  1. Judith Müller, Lukas Aeberhard & Theresia R. Kress
    Present address: Present addresses: Netherlands Cancer Institute (NKI), Department of Molecular Genetics, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands (J.M.); Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany (L.A.); European Institute of Oncology, IFOM-IEO Campus, Via Adamello, 16 - 20139 Milan, Italy (T.R.K.).,
  2. Lidan Liu and Jannes Ulbrich: These authors contributed equally to this work.

Authors and Affiliations

  1. Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany,
    Lidan Liu, Jannes Ulbrich, Judith Müller, Theresia R. Kress, Nathiya Muthalagu, Martin Eilers & Daniel J. Murphy
  2. Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany,
    Torsten Wüstefeld, Ramona Rudalska & Lars Zender
  3. Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany,
    Torsten Wüstefeld & Lars Zender
  4. Max-Delbrück-Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Robert Rössle Strasse 10, Berlin 13125, Germany,
    Lukas Aeberhard & Stefan Kempa
  5. Institute of Molecular Biology and Tumor Research, Emil-Mannkopff-Str. 2, 35037 Marburg, Germany,
    Lukas Rycak
  6. Institute for Pathology, University of Marburg, Baldingerstrasse, 35033 Marburg, Germany,
    Roland Moll

Authors

  1. Lidan Liu
  2. Jannes Ulbrich
  3. Judith Müller
  4. Torsten Wüstefeld
  5. Lukas Aeberhard
  6. Theresia R. Kress
  7. Nathiya Muthalagu
  8. Lukas Rycak
  9. Ramona Rudalska
  10. Roland Moll
  11. Stefan Kempa
  12. Lars Zender
  13. Martin Eilers
  14. Daniel J. Murphy

Contributions

L.L., J.U., J.M., T.R.K., N.M. and R.R. performed the experiments, R.M. analysed human tumour samples, and T.W. analysed the mouse model of HCC. L.A. and S.K. performed all metabolomic and proteomic analyses and questions regarding the technology should be addressed to S.K. L.R. performed bio-informatic analysis. L.Z., S.K., M.E. and D.J.M. designed experiments, and M.E. and D.J.M. wrote the paper.

Corresponding authors

Correspondence toMartin Eilers or Daniel J. Murphy.

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The authors declare no competing financial interests.

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Liu, L., Ulbrich, J., Müller, J. et al. Deregulated MYC expression induces dependence upon AMPK-related kinase 5.Nature 483, 608–612 (2012). https://doi.org/10.1038/nature10927

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Editorial Summary

Deregulated expression of the MYC oncogene is characteristic of many cancers. In an RNA interference screen designed to uncover genes that are crucial for cell survival specifically in MYC-driven tumour cells, Martin Eilers and colleagues have identified the kinase ARK5 as an important factor in MYC-mediated transformation. This is attributable to metabolic stress in MYC-expressing cells in which ARK5 is shown to be crucial for metabolic homeostasis and hence cell survival. ARK5 is also crucial in a MYC-driven mouse model of liver cancer. As a transcriptional regulator, MYC is difficult to target therapeutically, so ARK5 might prove to be an alternative target.