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, Bal L. Lokeshwar

Research output: Contribution to journalArticle

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

Fingerprint

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

  • Cancer Research
  • Oncology

Cite this

Araki, S., Omori, Y., Lyn, D., Singh, R. K., Meinbach, D. M., Sandman, Y., ... Lokeshwar, B. L. (2007). Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Research, 67(14), 6854-6862. https://doi.org/10.1158/0008-5472.CAN-07-1162

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, Bal L.

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

Research output: Contribution to journalArticle

Araki, S, Omori, Y, Lyn, D, Singh, RK, Meinbach, DM, Sandman, Y, Lokeshwar, VB & Lokeshwar, BL 2007, 'Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer', Cancer Research, vol. 67, no. 14, pp. 6854-6862. https://doi.org/10.1158/0008-5472.CAN-07-1162
Araki, Shinako ; Omori, Yohei ; Lyn, Dominic ; Singh, Rajendra K. ; Meinbach, David M. ; Sandman, Yekutiel ; Lokeshwar, Vinata B. ; Lokeshwar, Bal 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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