Journal article
AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival
Cell metabolism, Vol.23(4), pp.649-662
04/12/2016
DOI: 10.1016/j.cmet.2016.03.008
PMCID: PMC4832577
PMID: 27076078
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.
Details
- Title: Subtitle
- AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival
- Creators
- Rigel J Kishton - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USACarson E Barnes - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USAAmanda G Nichols - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USASivan Cohen - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USAValerie A Gerriets - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USAPeter J Siska - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN 37232, USAAndrew N Macintyre - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USAPankuri Goraksha-Hicks - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USAAguirre A de Cubas - Division of Hematology/Oncology, Department of Medicine, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USATingyu Liu - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USAMarc O Warmoes - Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USAE Dale Abel - Department of Medicine, University of Iowa, Iowa City, IA 52242, USAAllen Eng Juh Yeoh - Cancer Science Institute of Singapore, National University of Singapore, Singapore 119077, Singapore; Department of Pediatrics, National University Health System, Singapore 119228, SingaporeTimothy R Gershon - UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USAW Kimryn Rathmell - Division of Hematology/Oncology, Department of Medicine, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USAKristy L Richards - UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USAJason W Locasale - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USAJeffrey C Rathmell - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: jeff.rathmell@vanderbilt.edu
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.23(4), pp.649-662
- Publisher
- United States
- DOI
- 10.1016/j.cmet.2016.03.008
- PMID
- 27076078
- PMCID
- PMC4832577
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Grant note
- K24CA172355 / NCI NIH HHS R01 DK105550 / NIDDK NIH HHS R00 CA168997 / NCI NIH HHS K24 CA172355 / NCI NIH HHS R01CA123350 / NCI NIH HHS F31CA183529 / NCI NIH HHS T32 CA009582 / NCI NIH HHS R01 CA123350 / NCI NIH HHS P30 DK026687 / NIDDK NIH HHS R03 AI106835 / NIAID NIH HHS R00CA168997 / NCI NIH HHS P30 DK020541 / NIDDK NIH HHS T32 GM007105 / NIGMS NIH HHS F31 CA183529 / NCI NIH HHS R01 CA198482 / NCI NIH HHS R21 CA194829 / NCI NIH HHS R21CA194829 / NCI NIH HHS R03AI106835 / NIAID NIH HHS R01CA198482 / NCI NIH HHS
- Language
- English
- Date published
- 04/12/2016
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024518802771
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