Abstract
mTOR is a central regulator of cellular growth and metabolism. Using metabolic profiling and numerous small-molecule probes, we investigated whether mTOR affects immediate control over cellular metabolism by posttranslational mechanisms. Inhibiting the FKBP12/rapamycin-sensitive subset of mTOR functions in leukemic cells enhanced aerobic glycolysis and decreased uncoupled mitochondrial respiration within 25 min. mTOR is in a complex with the mitochondrial outer-membrane protein Bcl-xl and VDAC1. Bcl-xl, but not VDAC1, is a kinase substrate for mTOR in vitro, and mTOR regulates the association of Bcl-xl with mTOR. Inhibition of mTOR not only enhances aerobic glycolysis, but also induces a state of increased dependence on aerobic glycolysis in leukemic cells, as shown by the synergy between the glycolytic inhibitor 2-deoxyglucose and rapamycin in decreasing cell viability.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aniline Compounds / pharmacology
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Glycolysis / drug effects
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Humans
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / metabolism*
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Jurkat Cells
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Metabolome
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Oxygen Consumption / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism*
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Sirolimus / pharmacology
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Sulfonamides / pharmacology
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TOR Serine-Threonine Kinases
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Voltage-Dependent Anion Channel 1 / metabolism
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bcl-X Protein / metabolism
Substances
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Aniline Compounds
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BCL2L1 protein, human
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Intracellular Signaling Peptides and Proteins
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Sulfonamides
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VDAC1 protein, human
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bcl-X Protein
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Voltage-Dependent Anion Channel 1
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MTOR protein, human
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Sirolimus
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navitoclax