Unique induction of p21WAF1/CIP1 expression by vinorelbine in androgen-independent prostate cancer cells

X. M. Liu, J. D. Jiang, A. C. Ferrari, D. R. Budman, L. G. Wang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent (AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21 WAF1/CIP1 (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine (Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Sp1-3 and Sp1-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)1566-1573
Number of pages8
JournalBritish Journal of Cancer
Volume89
Issue number8
DOIs
StatePublished - Oct 20 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • Androgen-independent cell
  • Vinorelbine and paclitaxel
  • p21 induction
  • p21-deficit cell

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