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Deregulated MYC expression induces dependence upon AMPK-related kinase 5

Item Type:Article
Title:Deregulated MYC expression induces dependence upon AMPK-related kinase 5
Creators Name:Liu, L. and Ulbrich, J. and Mueller, J. and Wuestefeld, T. and Aeberhard, L. and Kress, T.R. and Muthalagu, N. and Rycak, L. and Rudalska, R. and Moll, R. and Kempa, S. and Zender, L. and Eilers, M. and Murphy, D.J.
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.
Keywords:Adenosine Triphosphate, AMP-Activated Protein Kinases, Animal Disease Models, Apoptosis, Cell Respiration, Cell Survival, Doxycycline, Electron Transport, Glutamine, Hepatocellular Carcinoma, Homeostasis, Liver Neoplasms, Neoplastic Cell Transformation, Neoplastic Gene Expression Regulation, Mitochondria, Myc Genes, Oncogene Protein p55(v-myc)/genetics, Oncogene Protein p55(v-myc)/metabolism, Protein Biosynthesis, Protein Kinases, Proteins, Repressor Proteins, RNA Interference, Signal Transduction, TOR Serine-Threonine Kinases, Tumor Cell Line, Animals, Mice
Publisher:Nature Publishing Group
Page Range:608-612
Date:29 March 2012
Official Publication:https://doi.org/10.1038/nature10927
PubMed:View item in PubMed

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