| Inappropriate Akt signaling enhances glycolysis and apoptosis resistance in a broad spectrum of human cancers. Interruptions in glucose metabolism are cytotoxic for cells with oncogenic activation of Akt, suggesting that regulators of glycolysis maybe be targeted for cancer therapy. We investigated the FoxO transcription factors and the protein kinases mTORC1 and S6Kinase 1 in their regulation of glycolysis downstream of Akt. S6 Kinase 1 knockdown in PTENdeficient cells suppressed glycolysis, suggesting that S6Kinase 1 positively regulates glycolysis downstream of activated Akt. On the other hand, FoxO3a knockdown was sufficient to induce glycolysis. Interestingly, elevated glycolysis in FoxO3a deficient cells was associated with increased mTORC1/S6 Kinase1 signaling. Enhanced mTORC1/S6Kinase 1 signaling in FoxO3a-knockdown cells was a consequence of decreased expression of the tumor suppressor TSC1 which functions with TSC2 to maintain low baseline activation of mTORC1. Transcription factor FoxO3a binds to and transactivates the TSC1 promoter, regulating the expression of TSC1 mRNA. Elevated glycolysis in FoxO3a-deficient cells was suppressed upon TSC1 reexpression as well as mTORC1 inhibition by rapamycin. Overall, we uncovered TSC1 as a novel target of FoxO3a thorough which FoxO3a regulates glycolysis downstream of Akt. |
