Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway

Biochem Biophys Res Commun. 2002 Jan 11;290(1):249-55. doi: 10.1006/bbrc.2001.6188.

Abstract

Cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. PGE(2) biosynthesis by cyclooxygenase (COX)-2 plays a pivotal role in inflammation and carcinogenesis. One of the critical proinflammatory cytokines in the prostate is interleukin-6 (IL-6). We hypothesized that increased expression of COX-2, with resultant increased levels of PGE(2) in human PIN cells, activates the IL-6 signaling pathway. We demonstrate an autocrine upregulation of PGE(2) mediated by IL-6 in a human PIN cell line. We further demonstrate that PGE(2) stimulates soluble IL-6 receptor (sIL-6R) release, gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity. These events, induced by PGE(2), lead to increased PIN cell growth. Treatment of PIN cells with a selective COX-2 inhibitor decreases cell growth. Finally, PGE(2)-stimulated PIN cell growth was abrogated by the addition of IL-6 neutralizing antibodies. These data provide mechanistic evidence that increased expression of COX-2/PGE(2) contributes to prostate cancer development and progression via activation of the IL-6 signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Cell Division
  • Cell Line
  • Cell Nucleus / metabolism
  • Culture Media, Conditioned / pharmacology
  • Cytokine Receptor gp130
  • DNA-Binding Proteins / metabolism*
  • Dimerization
  • Dinoprostone / biosynthesis*
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoblotting
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / metabolism*
  • Male
  • Membrane Glycoproteins / metabolism*
  • Phosphorylation
  • Precipitin Tests
  • Prostatic Intraepithelial Neoplasia / metabolism*
  • Prostatic Neoplasms / metabolism
  • STAT3 Transcription Factor
  • Signal Transduction
  • Time Factors
  • Trans-Activators / metabolism*
  • Up-Regulation

Substances

  • Antigens, CD
  • Culture Media, Conditioned
  • DNA-Binding Proteins
  • IL6ST protein, human
  • Interleukin-6
  • Membrane Glycoproteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Cytokine Receptor gp130
  • Dinoprostone