Requirement for NF-(kappa)B in interleukin-4-induced androgen receptor activation in prostate cancer cells

Prostate. 2005 Jul 1;64(2):160-7. doi: 10.1002/pros.20218.

Abstract

Background: Accumulating evidence suggest a critical role of activation of androgen receptor (AR) by nonandrogen in the development of androgen independent prostate cancer. Previous study identified that interleukin-4 (IL-4) enhances AR activation in the absence of androgen or in the very low levels of androgen in prostate cancer cells. In this study, the mechanism of IL-4-induced AR activation was investigated.

Methods & results: The induction of AR activation by IL-4 can be suppressed by expression of the I(kappa)B(alpha), an inhibitor of NF-(kappa)B. The enhanced expression of AR-mediated prostate-specific antigen (PSA) by IL-4 was blocked by the expression of I(kappa)B(alpha). IL-4 increases NF-(kappa)B transcriptional activity in prostate cancer cells which can be blocked by the addition of IL-4 antibody. IL-4 can also rapidly activate NF-kappaB. Furthermore, the IL-4-induced NF-kappaB activation and nuclear translocation can be blocked by LY294002, a PI3K/Akt specific inhibitor, suggesting that IL-4-induced NF-(kappa)B activation is mediated by activation of PI3K/Akt pathway.

Conclusion: In combination with previous study that IL-4 activates PI3K/Akt pathway, activation of PI3K/Akt > NF-(kappa)B pathways may be responsible for IL-4-induced AR activation in prostate cancer cells. Taken together, these studies suggest that IL-4 > PI3K/Akt > NF-(kappa)B signaling pathways, which activate AR signaling, may play an important role during the progression of androgen independent prostate cancer cells.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Interleukin-4 / physiology*
  • Male
  • NF-kappa B / physiology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Prostatic Neoplasms / physiopathology*
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Receptors, Androgen / physiology*
  • Signal Transduction

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins
  • Receptors, Androgen
  • Interleukin-4
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt