Abstract
Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas data revealed that AMPK isoforms are highly expressed in the lethal human cancer glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1α and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Video-Audio Media
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis
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Autophagy
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Brain Neoplasms / drug therapy
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Brain Neoplasms / enzymology*
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation* / drug effects
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Energy Metabolism* / drug effects
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Female
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GA-Binding Protein Transcription Factor / genetics
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GA-Binding Protein Transcription Factor / metabolism
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Gene Expression Regulation, Neoplastic
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Glioblastoma / drug therapy
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Glioblastoma / enzymology*
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Glioblastoma / genetics
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Glioblastoma / pathology
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HEK293 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Male
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Mice, Inbred NOD
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Mice, SCID
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / enzymology
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Neoplastic Stem Cells / pathology
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Protein Kinase Inhibitors / pharmacology
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Signal Transduction
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Time Factors
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Transcription, Genetic
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Tumor Burden
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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GA-Binding Protein Transcription Factor
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GABPA protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Protein Kinase Inhibitors
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PRKAB1 protein, human
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AMP-Activated Protein Kinases