Androgen and anti-androgen treatment modulates androgen receptor activity and DJ-1 stability

Prostate. 2006 Aug 1;66(11):1177-93. doi: 10.1002/pros.20450.

Abstract

Background: Mechanisms regulating the transition from hormone responsive to hormone refractory prostate cancer (PCa) have remained unclear.

Methods: We analyzed androgen and anti-androgen treatment on endogenous AR activity in primary human prostate epithelial (HPE) cells cultured directly from patient radical prostatectomy specimens utilizing a transiently infected gene reporter (TIGR) assay.

Results: Flutamide treatment exhibited agonist activities in HPE cells derived from tumor and non-tumor specimens which contained wild-type AR. After proteomic comparison of these cells to those where flutamide functioned normally as an antagonist, we identified DJ-1, a positive regulator of AR. DJ-1 expression increased in HPE and LNCaP cells during flutamide treatment as a result of DJ-1 protein stabilization.

Conclusion: Stabilization of AR and its co-regulators in the absence of androgen may partially account for anti-androgen withdrawal syndrome and potentially contribute to the development of hormone refractory PCa.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Androgens / pharmacology*
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Drug Stability
  • Electrophoresis, Gel, Two-Dimensional
  • Epithelial Cells / chemistry
  • Epithelial Cells / drug effects*
  • Epithelial Cells / ultrastructure
  • Flutamide / pharmacology
  • Gene Expression / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / analysis
  • Intracellular Signaling Peptides and Proteins / drug effects*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Microscopy, Electron
  • Oncogene Proteins / analysis
  • Oncogene Proteins / drug effects*
  • Oncogene Proteins / genetics
  • Prostate / chemistry
  • Prostate / drug effects*
  • Prostate / ultrastructure
  • Prostatic Neoplasms / chemistry
  • Prostatic Neoplasms / genetics
  • Protein Deglycase DJ-1
  • Receptors, Androgen / drug effects*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Androgen Antagonists
  • Androgens
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • Receptors, Androgen
  • Flutamide
  • PARK7 protein, human
  • Protein Deglycase DJ-1