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S6K1 mediates oncogenic glycolysis in Pten deficient leukemia

Tandon, Preeti

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
Hyperactive Akt signaling triggers glycolysis and apoptosis resistance in human cancer. Because sustained glycolysis is required for Akt dependent apoptosis resistance, we investigated the downstream signaling components that mediate Akt dependent increases in glycolysis in cells deficient for Pten, a negative regulator of the PI3K/Akt pathway. Genetic inactivation of the ribosomal protein S6 Kinase 1 (S6K1) in Pten-deficient cells prevented glycolysis, triggered Bax translocation and committed cells to apoptosis. Pharmacological S6K1 inhibition using a small molecule kinase inhibitor recapitulated the effects of genetically inactivating S6K1. Inactivation of S6K1 was associated with decreased expression of the pro-glycolytic HIF1a transcription factor. Restoring HIF1a expression was sufficient to restore both glycolysis and cell survival in S6K1-deficient cells. Conversely, inhibiting HIF1a expression in Pten deficient cells resulted in decreased glycolysis and cell survival, mimicking the loss of S6K1. In vivo, S6K1 deficiency delayed the development of lethal disease in a Pten deficient mouse model of leukemia. Thus, together the data suggest that S6K1 is a useful target for counteracting the metabolic program that supports apoptosis resistance in Pten-deficient cancers.
David Plas, PhD (Committee Chair)
Maria Czyzyk-Krzeska, MDPhD (Committee Member)
Angela Drew, PhD (Committee Member)
James Mulloy, PhD (Committee Member)
George Thomas, PhD (Committee Member)
125 p.

Recommended Citations

Citations

  • Tandon, P. (2011). S6K1 mediates oncogenic glycolysis in Pten deficient leukemia [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1320682200

    APA Style (7th edition)

  • Tandon, Preeti. S6K1 mediates oncogenic glycolysis in Pten deficient leukemia. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1320682200.

    MLA Style (8th edition)

  • Tandon, Preeti. "S6K1 mediates oncogenic glycolysis in Pten deficient leukemia." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1320682200

    Chicago Manual of Style (17th edition)