ABSTRACT
Pten inactivation promotes cell survival in leukemia cells by activating glycolytic metabolism. We found that targeting ribosomal protein S6 kinase 1 (S6K1) in Pten-deficient cells suppressed glycolysis and induced apoptosis. S6K1 knockdown decreased expression of HIF-1α, and HIF-1α was sufficient to restore glycolysis and survival of cells lacking S6K1. In the Pten(fl/fl) Mx1-Cre(+) mouse model of leukemia, S6K1 deletion delayed the development of leukemia. Thus, S6K1 is a critical mediator of glycolytic metabolism, cell survival, and leukemogenesis in Pten-deficient cells.
Subject(s)
Apoptosis , Glycolysis , Leukemia/enzymology , Neoplasm Proteins/metabolism , PTEN Phosphohydrolase/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Animals , Cell Line, Tumor , Disease Models, Animal , Gene Knockdown Techniques , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Leukemia/genetics , Mice , Mice, Knockout , Neoplasm Proteins/genetics , PTEN Phosphohydrolase/genetics , Ribosomal Protein S6 Kinases, 90-kDa/geneticsABSTRACT
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.