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

T S Mantoni1, G Reid, M D Garrett

  • 1Haddow Laboratories, Cancer Research, UK.

Oncogene
|January 26, 2006
PubMed

Insights

Genotoxic chemotherapeutic agents inhibit androgen receptor (AR) activity in prostate cancer cells. This occurs by preventing AR binding to DNA, independent of cell cycle or p53 status.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Androgen receptor (AR) signaling is crucial in prostate gland function and its deregulation is linked to prostate cancer.
  • Chemotherapeutic drugs used for advanced prostate cancer often induce genotoxic stress, such as DNA damage.

Purpose of the Study:

  • To investigate the effects of common chemotherapeutic genotoxic agents on AR function and expression.
  • To elucidate the mechanism by which genotoxic stress impacts AR activity.

Main Methods:

  • Utilized LNCaP cells, a human prostate cancer cell line.
  • Administered genotoxic agents etoposide and cisplatin.
  • Assessed AR activity, cell cycle distribution, subcellular localization, apoptosis, p53 function, and AR binding to androgen response elements.

Main Results:

  • Genotoxic agents etoposide and cisplatin inhibited endogenous AR activity in LNCaP cells.
  • This inhibition was not due to changes in cell cycle, AR localization, or apoptosis induction.
  • The inhibition of AR activity was independent of p53 function.
  • Genotoxic stress was found to inhibit the hormone-stimulated recruitment of AR to androgen response elements.

Conclusions:

  • Genotoxic stress from chemotherapeutic agents inhibits AR activity in prostate cancer cells.
  • A novel mechanism involving impaired AR binding to DNA is reported.
  • This finding provides new insights into the response of prostate cancer cells to chemotherapy.

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