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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / metabolism
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Cell Respiration
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Cell Survival
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Cell Transformation, Neoplastic / genetics
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Disease Models, Animal
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Doxycycline / pharmacology
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Electron Transport
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Gene Expression Regulation, Neoplastic*
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Genes, myc / genetics*
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Glutamine / metabolism
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Homeostasis
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Humans
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Liver Neoplasms / drug therapy
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mitochondria / metabolism
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Multiprotein Complexes
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Oncogene Protein p55(v-myc) / genetics
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Oncogene Protein p55(v-myc) / metabolism
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Protein Biosynthesis
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Protein Kinases / deficiency
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Proteins / antagonists & inhibitors
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Proteins / metabolism
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RNA Interference
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / deficiency
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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TOR Serine-Threonine Kinases / metabolism
Substances
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Multiprotein Complexes
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Oncogene Protein p55(v-myc)
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Proteins
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Repressor Proteins
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Glutamine
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Adenosine Triphosphate
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Protein Kinases
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NUAK1 protein, human
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NUAK1 protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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Doxycycline