Leptomycin B stabilizes and activates p53 in primary prostatic epithelial cells and induces apoptosis in the LNCaP cell line
- 17 January 2003
- journal article
- research article
- Published by Wiley in The Prostate
- Vol. 54 (4), 258-267
- https://doi.org/10.1002/pros.10197
Abstract
Background Previous studies showed that primary cultures of normal and malignant human prostatic epithelial cells are defective in their ability to upregulate the tumor suppressor protein p53 in response to DNA damage. This dysfunctional regulation of p53 may be relevant to both the high incidence of prostate cancer and its resistance to chemotherapy. Leptomycin B (LMB) has recently been found to increase the protein level and transcriptional activity of p53 by interfering with nucleocytoplasmic export and subsequent degradation by the proteasome. We investigated the ability of LMB to activate p53 in prostatic epithelial cells. Methods Primary cultures and the cell lines LNCaP and DU 145 were treated with LMB. p53 protein was evaluated in Western blots and by immunocytochemistry. Induction of downstream targets of p53 was evaluated in Western and Northern blots. Growth inhibition, cell cycle arrest, and apoptosis in response to LMB were measured in clonal growth assays, by flow cytometry, and by Hoescht/propidium iodide staining, respectively. Results Treatment of prostatic epithelial cells with LMB led to post-translational stabilization of p53, activation of downstream target genes, and induction of cell cycle arrest in primary cultures and apoptosis in LNCaP (with wild-type p53) but not DU 145 (with mutant p53) cells. Conclusions p53 in primary cultures of normal and malignant prostate cells, although dysfunctional in that it is not responsive to DNA damage, is activated by LMB. The ability of LMB to stabilize p53 and induce expression of p53-responsive growth inhibitory genes may be a useful lead in the development of chemopreventive or therapeutic small molecules that can modulate p53 function in prostatic epithelial cells. Prostate 54: 258–267, 2003.Keywords
This publication has 34 references indexed in Scilit:
- Relative frequency and morphology of cancers in carriers of germline TP53 mutationsOncogene, 2001
- Regulation of p53 FunctionExperimental Cell Research, 2001
- Effects on normal fibroblasts and neuroblastoma cells of the activation of the p53 response by the nuclear export inhibitor leptomycin BOncogene, 1999
- Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV lightOncogene, 1999
- An Inhibitor of Nuclear Export Activates the p53 Response and Induces the Localization of HDM2 and p53 to U1A-Positive Nuclear Bodies Associated with the PODsExperimental Cell Research, 1999
- Cancer statistics, 1999CA: A Cancer Journal for Clinicians, 1999
- Mdm2 promotes the rapid degradation of p53Nature, 1997
- WAF1, a potential mediator of p53 tumor suppressionCell, 1993
- The p53-mdm-2 autoregulatory feedback loop.Genes & Development, 1993
- An Abbreviated Standard Procedure for Accurate Tumor Volume Estimation in Prostate CancerThe American Journal of Surgical Pathology, 1992