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Androgen receptor activity is inhibited in response to genotoxic agents in a p53-independent manner

Oncogene volume 25, pages 3139–3149 (2006)Cite this article

Abstract

The androgen receptor (AR) is fundamental to androgen signalling within the prostate gland, and deregulation of its activity is frequently linked to the development of prostate cancer. Advanced prostate cancer is often treated with chemotherapy and most of these drugs exert their function by generating genotoxic stress such as DNA damage. We have investigated here the effects of genotoxic agents used in chemotherapeutic regimens on AR function and expression. We have discovered that endogenous AR activity in LNCaP cells is inhibited in response to the chemotherapeutic agents etoposide and cisplatin. This loss of AR activity is not caused by a change in cell cycle distribution, a change in subcellular localisation of the AR nor by induction of apoptosis. In addition, we found that inhibition of AR activity in response to genotoxic stress is independent of p53 function. Interestingly, our studies revealed that genotoxic stress inhibits the hormone-stimulated recruitment of AR to androgen response elements. Thus, we report for the first time a mechanism by which the AR activity is inhibited in response to different chemotherapeutic agents.

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Acknowledgements

We thank Jenny Titley for assistance with the flow cytometry analysis and Dr Elaine Barrie for fruitful discussions during the preparation of this manuscript. Cancer Research UK [CUK] Grant No. C309/A2187, The Danish Cancer Research Foundation, The Institute of Cancer Research, NCRI South of England Prostate Cancer Collaborative and a short-term EMBO fellowship have funded this work. The PSA61luc, pCMV β-gal and pSUPER constructs were kindly provided by Dr Jan Trapman (Erasmus University, The Netherlands), Dr Julia Bardos (Institute of Cancer Research, UK) and Professor Alan Ashworth (Institute of Cancer Research, UK), respectively. The PC3-wtAR cells were kindly provided by Professor Andrew Cato (Institute of Toxicology and Genetics, Karlsruhe, Germany).

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  1. Haddow Laboratories, Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Sutton, UK

    T S Mantoni & M D Garrett

  2. European Molecular Biology Laboratory, Heidelberg, Germany

    G Reid

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  1. T S Mantoni
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Correspondence to M D Garrett.

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Mantoni, T., Reid, G. & Garrett, M. Androgen receptor activity is inhibited in response to genotoxic agents in a p53-independent manner. Oncogene 25, 3139–3149 (2006). https://doi.org/10.1038/sj.onc.1209347

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