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FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1

Shikha Khatri1, Hasmik Yepiskoposyan, Catherine A Gallo

  • 1Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, Ohio 45267, USA.

The Journal of Biological Chemistry
|April 8, 2010
PubMed

Insights

The transcription factor FoxO3a regulates cancer cell glycolysis by controlling Tsc1 expression. Loss of FoxO3a increases glycolysis and apoptosis resistance, highlighting a new therapeutic target in cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Akt signaling promotes cancer cell survival and proliferation by increasing glycolysis and resistance to apoptosis.
  • FoxO transcription factors are key regulators of apoptosis downstream of Akt, but their role in glycolysis is unclear.

Purpose of the Study:

  • To investigate the role of FoxO transcription factors, specifically FoxO3a, in regulating Akt-induced glycolysis in cancer cells.
  • To elucidate the molecular mechanisms by which FoxO3a influences glycolysis and apoptosis resistance.

Main Methods:

  • FoxO3a knockdown in cancer cells.
  • Measurement of glycolysis rates and apoptosis.
  • Analysis of signaling pathways including mTORC1, S6K1, and TSC1.
  • Luciferase reporter assays to assess transcriptional activity on the TSC1 promoter.

Main Results:

  • FoxO3a knockdown led to increased glycolysis and apoptosis resistance.
  • Elevated glycolysis in FoxO3a-deficient cells was linked to mTORC1 activation and decreased TSC1 expression.
  • FoxO3a was found to directly bind and transactivate the TSC1 promoter, indicating transcriptional regulation.
  • Rapamycin treatment, an mTORC1 inhibitor, reduced glycolysis in FoxO3a-deficient cells.

Conclusions:

  • FoxO3a plays a critical role in regulating cancer cell glycolysis downstream of Akt signaling.
  • FoxO3a controls glycolysis by transcriptionally upregulating TSC1, which in turn inhibits mTORC1.
  • Targeting FoxO3a or its downstream effectors may offer novel therapeutic strategies for cancers driven by Akt signaling.

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