Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10418-23. doi: 10.1073/pnas.0704217104. Epub 2007 Jun 12.

Abstract

Androgen receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. A DNA-binding polyamide that targets the consensus androgen response element binds the prostate-specific antigen (PSA) promoter androgen response element, inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgens / pharmacology
  • Anilides / pharmacology
  • Base Pair Mismatch
  • Base Pairing
  • Base Sequence
  • Cell Line, Tumor
  • DNA / metabolism*
  • Dihydrotestosterone / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Male
  • Molecular Sequence Data
  • Nitriles / pharmacology
  • Nylons* / chemistry
  • Nylons* / metabolism
  • Nylons* / pharmacology
  • Phthalic Acids / chemistry
  • Promoter Regions, Genetic
  • Prostate-Specific Antigen / analysis
  • Prostate-Specific Antigen / genetics
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, Androgen / metabolism*
  • Response Elements / genetics
  • Tosyl Compounds / pharmacology

Substances

  • Androgen Antagonists
  • Androgens
  • Anilides
  • Nitriles
  • Nylons
  • Phthalic Acids
  • RNA, Messenger
  • Receptors, Androgen
  • Tosyl Compounds
  • Dihydrotestosterone
  • isophthalate
  • DNA
  • bicalutamide
  • Prostate-Specific Antigen

Associated data

  • GEO/GSE7708