Over-expression of IkappaB-kinase-epsilon (IKKepsilon/IKKi) induces secretion of inflammatory cytokines in prostate cancer cell lines

Prostate. 2009 May 15;69(7):706-18. doi: 10.1002/pros.20912.

Abstract

Background: Elevated inflammatory cytokine levels in serum have been associated with advanced stage metastasis-related morbidity in prostate cancer. Several studies have shown that IL-6 and IL-8 can accelerate the growth of human prostate cancer cell lines. Previous studies, in murine embryonic fibroblasts, have shown that Ikappa-B kinase-epsilon (IKKepsilon/IKKi)-deficiency results in the reduction of lipopolysaccharide-mediated expression of IL-6.

Results: In this study, we report that over-expression of IKKepsilon in hormone-sensitive 22Rv1 and LNCaP prostate cancer cells induces the secretion of several inflammatory cytokines including IL-6 and IL-8. Both of these cytokines are secreted by hormone-refractory PC-3 prostate cancer cells and IKKepsilon knock-down in these cells correlates with a strong decrease in IL-6 secretion. Furthermore, we demonstrate that IKKepsilon over-expression does not induce the activation of the IKKepsilon classical targets NF-kappaB and IRF-3, two transcription factors involved in the regulation of several cytokines. Finally, we observe that high IKKepsilon expression results in its nuclear translocation, a phenomena that is TBK1-independent.

Conclusions: This study identifies IKKepsilon as a potential prostate cancer gene that may favor chronic inflammation and create a tumor-supporting microenvironment that promotes prostate cancer progression, particularly by the induction of IL-6 secretion that may act as a positive growth factor in prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • I-kappa B Kinase / biosynthesis*
  • I-kappa B Kinase / genetics
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism*
  • Interleukin-8 / immunology
  • Interleukin-8 / metabolism*
  • Male
  • NF-kappa B / immunology
  • Neoplasms, Hormone-Dependent / enzymology
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / immunology
  • Neoplasms, Hormone-Dependent / metabolism
  • Plasmids / genetics
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / metabolism
  • Protein-Serine-Threonine Kinases / immunology
  • Transfection

Substances

  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase