The androgen receptor (AR) is the central component in regulation of the androgen signalling within the prostate gland. Deregulation of the AR activity is frequently involved in the development of prostate cancer. Treatment of advanced prostate cancer often involves chemotherapy and most of these drugs exert their function by generating genotoxic stress such as DNA damage. Although many cellular responses to DNA damage have been clarified over the past years, the effects of genotoxic stress on AR function remain to be elucidated. Here, the effects of genotoxic agents used in chemotherapeutic regimes were investigated in relation to endogenously expressed AR function in the hormone responsive prostate cancer cell line LNCaP. This led to the novel finding that the topoisomerase 11 inhibitors, etoposide and doxorubicin, and the DNA crosslinking agent, cisplatin, inhibited the AR activity. It was further discovered that this loss of AR activity could not be explained by changes in cell cycle distribution, altered nuclear translocation of the AR, reduced expression of the receptor or by induction of apoptosis. Activation of the tumour suppressor p53 is a central component in various cellular responses to genotoxic stress, however, the inhibition of AR activity in response to genotoxic stress was found to be mediated by a mechanism independent of p53 function. Etoposide reduced AR ligand binding within the first hour of androgen exposure, a response only observed to a minor degree after cisplatin treatment. In contrast, cisplatin caused a loss of serine 81 phosphorylation on the AR after 8 hours of drug exposure, which was a response not seen in etoposide treated cells. Interestingly, further studies revealed that at early timepoints both agents inhibited the hormone stimulated recruitment of AR to androgen response elements (AREs) in the promoter and enhancer regions of an AR regulated gene. A possible involvement of MAPK, P13K or cell cycle checkpoint signalling pathways was investigated, but none were found to be directly involved, however, preliminary studies suggest that fully functional HSP90 may be involved in this aspect of AR regulation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:429349 |
| Date | January 2006 |
| Creators | Mantoni, Tine S. |
| Publisher | Institute of Cancer Research (University Of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://publications.icr.ac.uk/9711/ |
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