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Carcinogenesis Advance Access originally published online on May 16, 2008
Carcinogenesis 2008 29(6):1148-1156; doi:10.1093/carcin/bgn109
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Angela Seaton, Paula Scullin, Pamela J. Maxwell, Catherine Wilson, Johanna Pettigrew, Rebecca Gallagher, Joe M. O'Sullivan, Patrick G. Johnston and David J. J. Waugh*

Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK

* To whom correspondence should be addressed. Tel: +44 2890 972760; Fax: +44 2890 972776; Email: d.waugh{at}qub.ac.uk

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.

Abbreviations: AIPC, androgen-independent prostate cancer; AR, androgen receptor; CaP, prostate cancer; Cdk2, cyclin-dependent kinase 2; CXCR, CXC chemokine receptor; DMSO, dimethyl sulphoxide; HEPES, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; IL, interleukin; JNK, c-jun N-terminal kinase; mRNA, messenger RNA; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PSA, prostate-specific antigen; qPCR, quantitative real-time polymerase chain reaction; rh-IL-8, recombinant human interleukin-8; TBS-T, Tris-buffered saline/0.1% Tween-20

Received December 20, 2007; revised April 11, 2008; accepted April 28, 2008.


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[Abstract] [Full Text] [PDF]


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