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Unique induction of p21(WAF1/CIP1)expression by vinorelbine in androgen-independent prostate cancer cells

X M Liu1, J D Jiang, A C Ferrari

  • 1Department of Medicine, Division of Medical Oncology, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1129, New York, NY 10029, USA.

British Journal of Cancer
|October 17, 2003
PubMed

Insights

Vinorelbine induces p21 expression in prostate cancer cells through p53-dependent and -independent pathways. This finding supports combining vinorelbine and paclitaxel for advanced prostate cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Cell Signaling

Background:

  • Hormone-refractory prostate cancer (HRPC) is characterized by androgen independence and apoptosis resistance.
  • Androgen-independent (AI) prostate cancer cells exhibit deficient p21(WAFl/CIP1) (p21) expression due to overexpressed androgen receptor (AR).

Purpose of the Study:

  • To investigate the differential induction of p53 and p21 expression by vinorelbine in hormone-dependent (AD) versus AI prostate cancer cells.
  • To elucidate the mechanisms underlying apoptotic signaling pathway differences between AD and AI cells.

Main Methods:

  • Comparison of vinorelbine-induced p53 and p21 expression in AD and AI prostate cancer cell lines.
  • Utilized deletion constructs of the p21 reporter gene to identify regulatory elements.
  • Assessed the effect of paclitaxel and vinorelbine combination therapy on AI cells.

Main Results:

  • Vinorelbine induced p21 expression in AD cells via a p53-dependent pathway.
  • In AI cells, vinorelbine restored p21 expression through both p53-dependent and -independent pathways.
  • The p53 binding sites Spl-3 and Spl-4 in the p21 promoter were crucial for vinorelbine-mediated p21 activation.
  • Paclitaxel alone did not induce p21 in AI cells, but its combination with vinorelbine showed synergistic effects.

Conclusions:

  • The study identified distinct mechanisms of p21 regulation by vinorelbine in hormone-dependent and -independent prostate cancer.
  • The findings support the synergistic potential of combining vinorelbine and paclitaxel for treating advanced prostate cancer.

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