Journal
NATURE
Volume 483, Issue 7391, Pages 608-U131Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10927
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Funding
- GROWTHSTOP consortium of the European Union
- Deutsche Forschungsgemeinschaft [Transregio 17, Transregio 77]
- Emmy Noether Programme [ZE 545/2-1]
- Bundesministerium fur Bildung und Forschung
- Senate of Berlin
- University of Wuerzburg Graduate School of Life Sciences and the Rebirth Cluster of Excellence
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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, andalters cellularmetabolismto enhance the provision of precursors for phospholipids and cellularmacromolecules(1,2). Here we showinhuman andmurine cell lines thatoncogenic levels ofMYC 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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