FoxA1 corrupts the antiandrogenic effect of bicalutamide but only weakly attenuates the effect of MDV3100 (Enzalutamide™)

Mol Cell Endocrinol. 2013 Jan 5;365(1):95-107. doi: 10.1016/j.mce.2012.10.002. Epub 2012 Oct 11.

Abstract

Prostate cancer growth depends on androgens. Synthetic antiandrogens are used in the cancer treatment. However, antiandrogens, such as bicalutamide (BIC), have a mixed agonist/antagonist activity. Here we compare the antiandrogenic capacity of BIC to a new antiandrogen, MDV3100 (MDV) or Enzalutamide™. By reconstitution of a hormone-regulated enhancer in Xenopus oocytes we show that both antagonists trigger the androgen receptor (AR) translocation to the nucleus, albeit with a reduced efficiency for MDV. Once in the nucleus, both AR-antagonist complexes can bind sequence specifically to DNA in vivo. The forkhead box transcription factor A (FoxA1) is a negative prognostic indicator for prostate cancer disease. FoxA1 expression presets the enhancer chromatin and makes the DNA more accessible for AR binding. In this context the BIC-AR antiandrogenic effect is seriously compromised as demonstrated by a significant chromatin remodeling and induction of a robust MMTV transcription whereas the MDV-AR complex displays a more persistent antagonistic character.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / adverse effects
  • Anilides / metabolism
  • Anilides / pharmacology*
  • Animals
  • Antineoplastic Agents, Hormonal / adverse effects
  • Antineoplastic Agents, Hormonal / metabolism
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Benzamides
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Chromatin Assembly and Disassembly / drug effects
  • Female
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 3-alpha / antagonists & inhibitors
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Humans
  • Male
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nitriles / adverse effects
  • Nitriles / metabolism
  • Nitriles / pharmacology*
  • Nonsteroidal Anti-Androgens / adverse effects
  • Nonsteroidal Anti-Androgens / metabolism
  • Nonsteroidal Anti-Androgens / pharmacology*
  • Oocytes / cytology
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / metabolism
  • Phenylthiohydantoin / pharmacology
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Transport / drug effects
  • RNA Interference
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Tosyl Compounds / adverse effects
  • Tosyl Compounds / metabolism
  • Tosyl Compounds / pharmacology*
  • Xenopus laevis

Substances

  • AR protein, human
  • Anilides
  • Antineoplastic Agents, Hormonal
  • Benzamides
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Neoplasm Proteins
  • Nitriles
  • Nonsteroidal Anti-Androgens
  • Receptors, Androgen
  • Recombinant Proteins
  • Tosyl Compounds
  • Phenylthiohydantoin
  • enzalutamide
  • bicalutamide