Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation

Carcinogenesis. 2008 Jun;29(6):1148-56. doi: 10.1093/carcin/bgn109. Epub 2008 May 16.


The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology
  • Anilides / pharmacology
  • Antineoplastic Agents, Hormonal / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / physiology*
  • Flow Cytometry
  • Humans
  • Interleukin-8 / metabolism*
  • Male
  • Nitriles / pharmacology
  • Prostatic Neoplasms / metabolism*
  • RNA, Small Interfering
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / metabolism*
  • Receptors, Interleukin-8B / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tosyl Compounds / pharmacology
  • Transfection


  • Androgen Antagonists
  • Anilides
  • Antineoplastic Agents, Hormonal
  • Interleukin-8
  • Nitriles
  • RNA, Small Interfering
  • Receptors, Androgen
  • Receptors, Interleukin-8B
  • Tosyl Compounds
  • bicalutamide