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

Shinako Araki, Yohei Omori, Dominic Lyn, Rajendra K. Singh, David M. Meinbach, Yekutiel Sandman, Vinata B Lokeshwar, Balakrishna L Lokeshwar

Research output: Contribution to journalArticle

175 Citations (Scopus)

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/106 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 κB (NF-κB) and showed increased survival when treated with docetaxel. This increase was blocked by NF-κB 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.

Original languageEnglish (US)
Pages (from-to)6854-6862
Number of pages9
JournalCancer Research
Volume67
Issue number14
DOIs
StatePublished - Jul 15 2007

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Interleukin-8
Androgens
Prostatic Neoplasms
Androgen Receptors
docetaxel
Neoplasms
Growth
Androgen Antagonists
Matrix Metalloproteinase 9
Microvessels
Chemokines
Immunoblotting
Vascular Endothelial Growth Factor A
Transfection
Complementary DNA
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. / Araki, Shinako; Omori, Yohei; Lyn, Dominic; Singh, Rajendra K.; Meinbach, David M.; Sandman, Yekutiel; Lokeshwar, Vinata B; Lokeshwar, Balakrishna L.

In: Cancer Research, Vol. 67, No. 14, 15.07.2007, p. 6854-6862.

Research output: Contribution to journalArticle

Araki, Shinako ; Omori, Yohei ; Lyn, Dominic ; Singh, Rajendra K. ; Meinbach, David M. ; Sandman, Yekutiel ; Lokeshwar, Vinata B ; Lokeshwar, Balakrishna L. / Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. In: Cancer Research. 2007 ; Vol. 67, No. 14. pp. 6854-6862.
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AU - Araki, Shinako

AU - Omori, Yohei

AU - Lyn, Dominic

AU - Singh, Rajendra K.

AU - Meinbach, David M.

AU - Sandman, Yekutiel

AU - Lokeshwar, Vinata B

AU - Lokeshwar, Balakrishna L

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