Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway

Oncogene. 2003 Sep 11;22(39):7981-8. doi: 10.1038/sj.onc.1206735.

Abstract

Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgen-responsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pM of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.

Publication types

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

MeSH terms

  • Androgen Antagonists / pharmacology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Chromones / pharmacology
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism
  • Enzyme Inhibitors / pharmacology
  • Flutamide / pharmacology
  • Gene Expression / drug effects
  • Humans
  • Interleukin-4 / metabolism
  • Interleukin-4 / pharmacology*
  • Male
  • Metribolone / pharmacology
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Prostate-Specific Antigen / drug effects
  • Prostate-Specific Antigen / genetics
  • Prostate-Specific Antigen / metabolism*
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / drug effects
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Response Elements / drug effects
  • Signal Transduction / drug effects*
  • Testosterone Congeners / pharmacology
  • Tumor Cells, Cultured

Substances

  • Androgen Antagonists
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Androgen
  • Testosterone Congeners
  • Interleukin-4
  • Metribolone
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Flutamide
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Prostate-Specific Antigen