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Androgens negatively regulate forkhead transcription factor FKHR (FOXO1) through a proteolytic mechanism in prostate

Haojie Huang1, David C Muddiman, Donald J Tindall

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

The Journal of Biological Chemistry
|January 17, 2004
PubMed

Insights

Androgens protect prostate cancer cells by cleaving the FKHR (FOXO1) protein. This cleavage, mediated by an acidic cysteine protease, reduces FKHR

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Androgens are known to inhibit apoptosis in prostate cells, but the mechanisms remain unclear.
  • Forkhead transcription factor FKHR (FOXO1) induces cell death in prostate cancer cells.
  • Understanding androgen-mediated cell survival pathways is crucial for prostate cancer treatment.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which androgens inhibit apoptosis in prostate cancer cells.
  • To investigate the role of FKHR (FOXO1) in androgen-mediated regulation of cell death.
  • To identify the specific protease involved in androgen-induced FKHR (FOXO1) processing.

Main Methods:

  • Treatment of LNCaP cells with synthetic androgen R1881.
  • Analysis of FKHR (FOXO1) protein levels, transcriptional activity, and cleavage products using Western blotting and mass spectrometry.
  • Inhibition studies using lysosomal acidic cysteine protease inhibitors and site-directed mutagenesis.

Main Results:

  • Androgen R1881 blocked FKHR (FOXO1)-induced cell death and reduced FKHR (FOXO1) transcriptional activity.
  • R1881 treatment decreased intact 70 kDa FKHR (FOXO1) and increased a 60 kDa cleavage product.
  • The 60 kDa product resulted from cleavage at Arg(537), mediated by an androgen-activated acidic cysteine protease.

Conclusions:

  • Androgens protect prostate cancer cells by inducing cleavage of FKHR (FOXO1) via an acidic cysteine protease.
  • This cleavage abrogates FKHR (FOXO1)'s cell death-inducing activity, providing a novel mechanism for androgen-mediated survival.
  • Targeting this protease pathway could offer new therapeutic strategies for prostate cancer.

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