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IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

Mickey C-T Hu1, Dung-Fang Lee, Weiya Xia

  • 1Department of Molecular and Cellular Oncology, The University of Texas, Houston, TX 77030, USA. michu@mdanderson.org

Cell
|April 16, 2004
PubMed

Insights

Nuclear exclusion of FOXO3a, typically regulated by Akt, can also occur independently via IKK. This IKK-mediated pathway promotes cell proliferation and tumorigenesis, impacting breast cancer survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The forkhead transcription factor FOXO3a is normally excluded from the nucleus by Akt, promoting cell survival.
  • Previous understanding linked FOXO3a nuclear exclusion solely to Akt phosphorylation.

Purpose of the Study:

  • To investigate the pathological relationship between phosphorylated-Akt (Akt-p) and FOXO3a in primary tumors.
  • To identify alternative mechanisms regulating FOXO3a localization beyond Akt signaling.

Main Methods:

  • Analysis of primary tumors to assess Akt-p and FOXO3a localization.
  • In vitro experiments demonstrating IkappaB kinase (IKK) interaction with, phosphorylation of, and inhibition of FOXO3a.
  • Investigation of FOXO3a proteolysis via the Ub-dependent proteasome pathway.
  • Correlation analysis of cytoplasmic FOXO3a with IKKbeta or Akt-p expression.
  • Assessment of IKKbeta's effect on cell proliferation and tumorigenesis, and the role of FOXO3a in this process.

Main Results:

  • FOXO3a was found excluded from the nucleus in some tumors lacking Akt-p, indicating an Akt-independent mechanism.
  • IkappaB kinase (IKK) was shown to physically interact with, phosphorylate, and inhibit FOXO3a independently of Akt.
  • IKK-mediated inhibition of FOXO3a leads to its proteolysis via the Ub-dependent proteasome pathway.
  • Cytoplasmic FOXO3a correlates with IKKbeta or Akt-p expression and is associated with poor survival in breast cancer.
  • Constitutive IKKbeta expression promotes cell proliferation and tumorigenesis, effects that can be counteracted by FOXO3a.

Conclusions:

  • IkappaB kinase (IKK) represents a novel pathway for the negative regulation of FOXO3a localization and function.
  • This IKK-mediated cytoplasmic localization of FOXO3a is a key mechanism promoting cell growth and tumorigenesis.
  • The findings reveal a critical role for IKK in cancer development, independent of the well-established Akt pathway.

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