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p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells

Srirupa Roy1, Manjinder Kaur, Chapla Agarwal

  • 1Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East Ninth Street, Box C238, Denver, CO 80262, USA.

Molecular Cancer Therapeutics
|October 17, 2007
PubMed

Insights

Silibinin halts prostate cancer cell growth by increasing p21 and p27 protein levels. This study reveals silibinin

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Silibinin is known to induce cell cycle arrest (G1 arrest) in prostate cancer cells.
  • The precise mechanisms and biological significance of p21/Cip1 and p27/Kip1 induction by silibinin remain unclear.
  • Prostate cancer cell lines DU145 (androgen-independent) and 22Rv1 (androgen-dependent) were used to investigate these effects.

Purpose of the Study:

  • To investigate the role of p21 and p27 induction in silibinin-mediated G1 arrest in prostate cancer cells.
  • To elucidate the underlying molecular mechanisms of p21 and p27 induction by silibinin.
  • To determine the contribution of Skp2 in silibinin's effects on cell cycle regulation.

Main Methods:

  • RNA interference was used to silence p21 and p27 expression.
  • Cycloheximide-chase experiments assessed protein stability.
  • Western blotting and quantitative PCR analyzed protein and mRNA levels, respectively.
  • Promoter activity assays and small interfering RNA (siRNA) transfections were employed to study regulatory mechanisms.

Main Results:

  • Silencing p21 and p27 individually partially reversed G1 arrest; simultaneous silencing showed additional reversal in 22Rv1 cells.
  • Silibinin increased the protein half-life of p21 and p27 by reducing Skp2 levels and its binding to these proteins.
  • Silibinin also increased p21 and p27 mRNA levels and promoter activity, indicating transcriptional regulation.
  • Skp2 knockdown attenuated silibinin-induced G1 arrest and p21/p27 induction.

Conclusions:

  • p21 and p27 induction are essential for silibinin-mediated G1 arrest in prostate cancer cells, with cell-specific variations in their relative importance.
  • Silibinin employs both post-translational (via Skp2 regulation) and transcriptional mechanisms to increase p21 and p27 levels.
  • These findings identify a critical role for p21 and p27 regulation in silibinin's anti-cancer effects on prostate cancer cells.

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