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Inhibition of p53 function diminishes androgen receptor-mediated signaling in prostate cancer cell lines

Oncogene volume 23, pages 3541–3549 (2004)Cite this article

Abstract

Current therapy for advanced prostate cancer is mainly based on androgen deprivation, although most patients relapse to androgen-insensitive disease. Several mechanisms contributing to androgen-independent growth including alterations in the structure or expression of the androgen receptor (AR) and its cofactors have been identified. Recent evidence suggests that p53 is involved in androgen signaling. The analysis of the effect of p53 on androgen signaling was performed in 22Rv1 and LNCaP prostate cancer cells that express both p53 and AR. The overexpression of p53 diminished the androgenic response in both cell lines in a reporter gene assay. Conversely, the inhibition of p53 by three different p53 inhibitors, Pifithrin-1α (PFT-1α), an inhibitor of p53-dependent transactivation; MDM2, a regulator of p53 expression; and a dominant-negative N-terminally truncated p53 gene also reduced transactivation of androgen-dependent reporter genes. The inactivation of p53 by PFT-1α decreased AR-protein expression in both 22Rv1 and LNCaP cells. Our findings confirm that the overexpression of wild-type p53 decreases androgen function, whereas p53 expression at physiological levels stabilizes AR signaling. Thus, our findings suggest that there is a balance of AR and p53 expression during the androgen-dependent growth of prostate cancer, which is obliterated during further progression of the disease.

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Acknowledgements

We thank Dr A Baniahmad, Dr Z Culig, Dr M Oren, Dr J Trappman and Dr B Vogelstein for kindly providing plasmid constructs used in this study. This work was supported by the Forschungskomission der Medizinischen Fakultät der Heinrich-Heine Universität, Düsseldorf and Action Lions – Vaincre le Cancer, Luxembourg.

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  1. Department of Urology, Heinrich-Heine University, Düsseldorf, D-40225, Germany

    Marcus V Cronauer, Wolfgang A Schulz, Tatjana Burchardt, Rolf Ackermann & Martin Burchardt

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  1. Marcus V Cronauer
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  2. Wolfgang A Schulz
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Correspondence to Martin Burchardt.

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Cronauer, M., Schulz, W., Burchardt, T. et al. Inhibition of p53 function diminishes androgen receptor-mediated signaling in prostate cancer cell lines. Oncogene 23, 3541–3549 (2004). https://doi.org/10.1038/sj.onc.1207346

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