Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation
Open Access
- 15 April 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 29 (6), 1148-1156
- https://doi.org/10.1093/carcin/bgn109
Abstract
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.Keywords
This publication has 32 references indexed in Scilit:
- Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate Tumor CellsMolecular and Cellular Biology, 2006
- Mechanisms Underlying the Development of Androgen-Independent Prostate CancerClinical Cancer Research, 2006
- Nonapical and Cytoplasmic Expression of Interleukin-8, CXCR1, and CXCR2 Correlates with Cell Proliferation and Microvessel Density in Prostate CancerClinical Cancer Research, 2005
- Expression of interleukin‐8 gene in radical prostatectomy specimens is associated with advanced pathologic stageThe Prostate, 2005
- Mechanisms of Androgen-Refractory Prostate CancerNew England Journal of Medicine, 2004
- Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAKOncogene, 2004
- Molecular determinants of resistance to antiandrogen therapyNature Medicine, 2003
- Androgen receptor: A key molecule in the progression of prostate cancer to hormone independenceJournal of Cellular Biochemistry, 2003
- Neuropeptide-Induced Androgen Independence in Prostate Cancer Cells: Roles of Nonreceptor Tyrosine Kinases Etk/Bmx, Src, and Focal Adhesion KinaseMolecular and Cellular Biology, 2001
- Expression of Interleukin-8 Correlates with Angiogenesis, Tumorigenicity, and Metastasis of Human Prostate Cancer Cells Implanted Orthotopically in Nude MiceNeoplasia, 2001