Abstract
Akt signal transduction induces coordinated increases in glycolysis and apoptosis resistance in a broad spectrum of cancers. Downstream of Akt, the FoxO transcription factors regulate apoptosis via Bim, but the contributions of FoxOs in regulating Akt-induced glycolysis are not well described. We find that FoxO3a knockdown is sufficient to induce apoptosis resistance in conjunction with elevated glycolysis. Glycolysis in FoxO3a-deficient cells was associated with increased S6K1 phosphorylation and was sensitive to rapamycin, an inhibitor of the mTORC1 pathway that has been linked to glycolysis regulation. We show that mTORC1-dependent glycolysis is increased in FoxO3a knockdown cells due to decreased expression of the TSC1 tumor suppressor that opposes mTORC1 activation. FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Glycolysis / drug effects
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Glycolysis / physiology*
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Humans
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Immunosuppressive Agents / pharmacology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Multiprotein Complexes
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Promoter Regions, Genetic / physiology
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Proteins
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Ribosomal Protein S6 Kinases / genetics
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Ribosomal Protein S6 Kinases / metabolism
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology*
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology*
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins / biosynthesis*
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Tumor Suppressor Proteins / genetics
Substances
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Immunosuppressive Agents
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Multiprotein Complexes
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Proteins
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TSC1 protein, human
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Transcription Factors
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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Sirolimus