Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer

Cancer Res. 2007 Jul 15;67(14):6854-62. doi: 10.1158/0008-5472.CAN-07-1162.

Abstract

The proinflammatory chemokine interleukin-8 (IL-8) is undetectable in androgen-responsive prostate cancer cells (e.g., LNCaP and LAPC-4), but it is highly expressed in androgen-independent metastatic cells, such as PC-3. In this report, we show IL-8 functions in androgen independence, chemoresistance, tumor growth, and angiogenesis. We stably transfected LNCaP and LAPC-4 cells with IL-8 cDNA and selected IL-8-secreting (IL8-S) transfectants. The IL8-S transfectants that secreted IL-8 at levels similar to that secreted by PC-3 cells (100-170 ng/10(6) cells) were characterized. Continuous or transient exposure of LNCaP and LAPC-4 cells to IL-8 reduced their dependence on androgen for growth and decreased sensitivity (>3.5x) to an antiandrogen. IL-8-induced cell proliferation was mediated through CXCR1 and was independent of androgen receptor (AR). Quantitative PCR, immunoblotting, and transfection studies showed that IL8-S cells or IL-8-treated LAPC-4 cells exhibit a 2- to 3-fold reduction in PSA and AR levels, when compared with vector transfectants. IL8-S cells expressed 2- to 3-fold higher levels of phospho-EGFR, src, Akt, and nuclear factor kappaB (NF-kappaB) and showed increased survival when treated with docetaxel. This increase was blocked by NF-kappaB and src inhibitors, but not by an Akt inhibitor. IL8-S transfectants displayed a 3- to 5-fold increased motility, invasion, matrix metalloproteinase-9 and vascular endothelial growth factor production. LNCaP IL8-S cells grew rapidly as tumors, with increased microvessel density and abnormal tumor vasculature when compared with the tumors derived from their vector-transfected counterparts. Therefore, IL-8 is a molecular determinant of androgen-independent prostate cancer growth and progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgens / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-8 / metabolism*
  • Male
  • Mice
  • Mice, Nude
  • NF-kappa B / metabolism
  • Prostatic Neoplasms / metabolism*
  • Receptors, Androgen / metabolism*
  • Recombinant Proteins / chemistry

Substances

  • Androgens
  • Interleukin-8
  • NF-kappa B
  • Receptors, Androgen
  • Recombinant Proteins