Deregulated MYC expression induces dependence upon AMPK-related kinase 5

Lidan Liu, Jannes Ulbrich, Judith Müller, Torsten Wüstefeld, Lukas Aeberhard, Theresia R. Kress, Nathiya Muthalagu, Lukas Rycak, Ramona Rudalska, Roland Moll, Stefan Kempa, Lars Zender, Martin Eilers, Daniel J. Murphy

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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 macromolecules. 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.

Original languageEnglish
Pages (from-to)608-612
Number of pages5
JournalNature
Volume483
Issue number7391
DOIs
Publication statusPublished - Mar 29 2012

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Liu, L., Ulbrich, J., Müller, J., Wüstefeld, T., Aeberhard, L., Kress, T. R., Muthalagu, N., Rycak, L., Rudalska, R., Moll, R., Kempa, S., Zender, L., Eilers, M., & Murphy, D. J. (2012). Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature, 483(7391), 608-612. https://doi.org/10.1038/nature10927