Unique induction of p21 expression by vinorelbine in androgen-independent prostate cancer cells

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(WAFl/CIP1)...

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Bibliographic Details
Published in:British journal of cancer 2003-10, Vol.89 (8), p.1566-1573
Main Authors: Liu, X M, Jiang, J D, Ferrari, A C, Budman, D R, Wang, L G
Format: Article
Language:English
Subjects:
Androgen Antagonists - pharmacology
Animals
Antineoplastic Agents, Phytogenic - pharmacology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - biosynthesis
Cyclins - pharmacology
Drug Interactions
Drug Resistance, Neoplasm
Drug Therapy, Combination
Enzyme Inhibitors - pharmacology
Gene Deletion
Gene Expression Regulation, Neoplastic - drug effects
Male
Paclitaxel - pharmacology
Prostatic Neoplasms - pathology
Tumor Cells, Cultured
Vinblastine - analogs & derivatives
Vinblastine - pharmacology
Vinorelbine
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Summary: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(WAFl/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, Spl-3 and Spl-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.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6601317