Androgen receptor activity is inhibited in response to genotoxic agents in a p53-independent manner.
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.
Mantoni
T S
TS
Haddow Laboratories, Cancer Research, UK.
Reid
G
G
Garrett
M D
MD
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D009376:Neoplasms, Hormone-Dependent; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D008024:Ligands; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; D013196:Dihydrotestosterone; D005047:Etoposide; D002945:Cisplatin