Carcinogenesis Advance Access published online on May 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn109
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INTERLEUKIN-8 SIGNALING PROMOTES ANDROGEN-INDEPENDENT PROLIFERATION OF PROSTATE CANCER CELLS VIA INDUCTION OF ANDROGEN RECEPTOR EXPRESSION AND ACTIVATION.
Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland
1 To whom reprint requests should be addressed: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland. Tel: (0)2890-972760, Fax: (0)2890-972776, Email: d.waugh{at}qub.ac.uk
The aim of our study was to assess the importance of the CXC chemokine, interleukin-8 (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 IL-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the mRNA and protein level, assessed by quantitative PCR and immunoblotting, respectively. Using an ARE-luciferase construct we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent up-regulation of PSA and Cdk2 mRNA transcript levels in LNCaP cells. Blockade of CXC-chemokine receptor-2 (CXCR2) signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8 induced increases in AR expression and transcriptional activity. Furthermore, in MTT assays, co-administration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data shows 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 shows that IL-8 promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.
Key Words: Interleukin-8 (IL-8) • Androgen receptor • PSA • Bicalutamide • Prostate Cancer
Received December 20, 2007; revised April 11, 2008; accepted April 28, 2008.
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