Mullerian inhibiting substance regulates androgen-induced gene expression and growth in prostate cancer cells through a nuclear factor-kappaB-dependent Smad-independent mechanism

Mol Endocrinol. 2006 Oct;20(10):2382-91. doi: 10.1210/me.2005-0480. Epub 2006 Jun 1.

Abstract

Mullerian inhibiting substance (MIS), a member of the TGFbeta superfamily, causes regression of the Mullerian duct in male embryos. The presence of MIS type II and type I receptors in tissues and cell lines derived from the prostate suggests that prostate is a likely target for MIS. In this report, we demonstrate that MIS inhibits androgen-stimulated growth of LNCaP cells and decreases their survival in androgen-deprived medium by preventing cell cycle progression and inducing apoptosis. Expression of dominant-negative Smad1 reversed the ability of MIS to decrease LNCaP cell survival in androgen-deprived medium but not androgen-stimulated growth, whereas abrogation of nuclear factor-kappaB (NFkappaB) activation ablated the suppressive effects of MIS on both androgen-stimulated growth and androgen-independent survival. The effect of MIS on androgen-induced growth was not due to changes in androgen receptor expression. However, MIS suppressed androgen-stimulated transcription of prostate-specific antigen; ablation of NFkappaB activation reversed MIS-mediated suppression of prostate-specific antigen. These observations suggest that MIS regulates androgen-induced gene expression and growth in prostate cancer cells through a NFkappaB-dependent but Smad1-independent mechanism. Thus, MIS, in addition to potentially regulating prostate growth indirectly by suppressing testicular testosterone synthesis, may also be a direct regulator of androgen-induced gene expression and growth in the prostate at the cellular level.

Publication types

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

MeSH terms

  • Androgens / metabolism*
  • Anti-Mullerian Hormone
  • Apoptosis / physiology
  • Blotting, Northern
  • Blotting, Western
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Glycoproteins / metabolism*
  • Humans
  • Luciferases
  • Male
  • NF-kappa B / metabolism*
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / physiopathology
  • Smad1 Protein / metabolism*
  • Testicular Hormones / metabolism*

Substances

  • Androgens
  • Glycoproteins
  • NF-kappa B
  • SMAD1 protein, human
  • Smad1 Protein
  • Testicular Hormones
  • Anti-Mullerian Hormone
  • Luciferases
  • Prostate-Specific Antigen