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Par-4-dependent apoptosis by the dietary compound withaferin A in prostate cancer cells

Sowmyalakshmi Srinivasan1, Rama S Ranga, Ravshan Burikhanov

  • 1Department of Clinical Sciences, College of Health Sciences, University of Kentucky, 900 South Limestone Street, Lexington, KY 40536, USA.

Cancer Research
|December 23, 2006
PubMed

Insights

Withaferin A, a natural compound, induces cancer cell death by activating the Par-4 gene. This offers a new therapeutic strategy for prostate cancer, even when resistant to standard treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Prostate tumors with androgen receptor (AR) mutations or deletions resist apoptosis induced by androgen ablation therapy.
  • There is a critical need for novel therapeutics that can induce apoptosis irrespective of AR status in prostate cancer cells.

Purpose of the Study:

  • To identify dietary herbal compounds that can induce apoptosis in prostate cancer cells, regardless of AR status.
  • To investigate the mechanism of action of Withaferin A (WA) in inducing apoptosis via the prostate apoptosis response-4 (Par-4) gene.

Main Methods:

  • Screened dietary herbal compounds using a reporter assay for the Par-4 gene.
  • Tested Withaferin A (WA) in androgen-refractory and androgen-responsive prostate cancer cells.
  • Utilized PC-3 xenograft models in nude mice to assess tumor regression.
  • Investigated the role of AR status by restoring wild-type AR in AR-negative cells.

Main Results:

  • Withaferin A (WA) induced Par-4-dependent apoptosis in androgen-refractory prostate cancer cells and caused PC-3 xenograft regression.
  • Restoration of AR in AR-negative cells abrogated WA-induced Par-4 and apoptosis.
  • WA and anti-androgens synergistically induced Par-4 and apoptosis in androgen-responsive cells when combined.

Conclusions:

  • Withaferin A, in combination with anti-androgens, effectively inhibits survival in both androgen-responsive and androgen-refractory prostate cancer cells via a Par-4-dependent mechanism.
  • This study highlights the potential of WA as a therapeutic agent for prostate cancer, offering a strategy effective against therapy-resistant tumors.
  • The findings support the extension of Par-4 up-regulation strategies to high-throughput screens for identifying synergistic combinations for various cancer types.

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