Androgen and its receptor promote Bax-mediated apoptosis

Mol Cell Biol. 2006 Mar;26(5):1908-16. doi: 10.1128/MCB.26.5.1908-1916.2006.

Abstract

Androgen and its receptor (AR) have been reported to have pro- or antiapoptotic functions. However, the underlying molecular mechanism is incompletely understood. We report here that androgen and AR promote Bax-mediated apoptosis in prostate cancer cells. UV irradiation and ectopic expression of Bax induce apoptosis in AR-positive, but not AR-negative prostate cancer cells. UV- and Bax-induced apoptosis is abrogated in AR-positive cells that express small interference RNA (siRNA) of AR and is sensitized by reintroduction of AR into AR-negative cells. Although AR is able to promote Bax-mediated apoptosis independently of androgen, the promotion by AR can be further potentiated by androgen via AR-dependent transcription activation. AR is essential for the translocation of Bax to mitochondria in UV- or Bax-induced apoptosis. Inhibition of Bax expression by Bax siRNA suppresses UV-induced apoptosis in AR-positive cells. In addition, introduction of AR into AR-negative prostate cancer cells upregulates expression levels of the BH3-only protein Noxa, whereas inhibition of Noxa expression reduces the promotion by AR on UV-induced apoptosis. Thus, our results reveal a novel cross talk between the androgen/AR hormonal signaling pathway and the intrinsic apoptotic death pathway that determines the sensitivity of stress-induced apoptosis in prostate cancer cells.

Publication types

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

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgens / metabolism
  • Androgens / pharmacology*
  • Anilides / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Humans
  • Male
  • Metribolone / pharmacology
  • Mitochondria / metabolism
  • Nitriles
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Protein Transport
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / metabolism*
  • Tosyl Compounds
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Ultraviolet Rays
  • bcl-2-Associated X Protein / drug effects
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*

Substances

  • Androgen Antagonists
  • Androgens
  • Anilides
  • BAX protein, human
  • Nitriles
  • PMAIP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Androgen
  • Tosyl Compounds
  • bcl-2-Associated X Protein
  • Metribolone
  • bicalutamide