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Chemical Biology Program, Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142
Contributed by Stuart L. Schreiber, October 22, 2009
Received for publication September 28, 2009.
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 overcellular metabolism by posttranslational mechanisms. Inhibitingthe FKBP12/rapamycin-sensitive subset of mTOR functions in leukemiccells enhanced aerobic glycolysis and decreased uncoupled mitochondrialrespiration within 25 min. mTOR is in a complex with the mitochondrialouter-membrane protein Bcl-xl and VDAC1. Bcl-xl, but not VDAC1,is a kinase substrate for mTOR in vitro, and mTOR regulatesthe association of Bcl-xl with mTOR. Inhibition of mTOR notonly enhances aerobic glycolysis, but also induces a state ofincreased dependence on aerobic glycolysis in leukemic cells,as shown by the synergy between the glycolytic inhibitor 2-deoxyglucoseand rapamycin in decreasing cell viability.
Key Words: metabolomics mitochondria chemical biology
Freely available online through the PNAS open access option.
Author contributions: A.R. and S.L.S. designed research; A.R.performed research; A.R. and S.L.S. analyzed data; and A.R.and S.L.S. wrote the paper.