Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK

Authors

Li-Fen Lee, Department of Microbiology and Immunology, Stanford University, School of Medicine, Stanford
Maggie Louie, Department of Biological Chemistry and Cancer Center, University of California at DavisFollow
Sonal J. Desai, Department of Biological Chemistry and Cancer Center, University of California at Davis
Joy Yang, Department of Urology, University of California at Davis
Hong-Wu Chen, Department of Biological Chemistry and Cancer Center, University of California at DavisFollow
Christopher P. Evans, Department of Urology, University of California at Davis
Hsing-Jien Kung, Department of Biological Chemistry and Cancer Center, University of California at DavisFollow

Document Type

Article

Source

Oncogene

ISSN

0950-9232

Volume

23

Issue

12

First Page

2197

Last Page

2205

Publication Date

2004

Department

Natural Sciences and Mathematics

Abstract

Interleukin-8 (IL-8), a chemokine implicated in the metastasis and angiogenesis of a variety of cancers, has been reported to be overexpressed in prostate cancer. In this study, we ascribe a new role for IL-8 in prostate cancer progression using LNCaP cells. We demonstrate that IL-8 activates the androgen receptor and confers androgen-independent growth, while serving as a potent chemotactic factor. Our evaluation of the possible signal pathways involved in androgen-independence and cell migration shows that the tyrosine kinases Src and FAK (focal adhesion kinase) are involved in IL-8-induced signaling. Pharmacological and genetic inhibitors of Src and FAK interfere with IL-8-induced cell migration, while only the Src inhibitor was able to repress androgen-independent growth. This suggests that both growth and migration depend on the activity of Src, whereas cell migration also requires the activation of FAK. Our evidence that IL-8-induced androgen-independent growth is, at least in part, due to androgen receptor activation includes (1) an inhibitor of androgen receptor activity diminishes cell growth; (2) androgen receptor transactivation potential is augmented by IL-8 and (3) androgen receptor is recruited to the promoter of prostate specific antigen (PSA) upon IL-8 treatment, based on chromatin immunoprecipitation experiments. Taken together, our data suggest that in addition to its role in metastasis and angiogenesis, IL-8 may also serve as a facilitator for androgen-independent transition of prostate cancers. To our knowledge, this is the first report about the tyrosine kinase signals and androgen receptor activation induced by IL-8 in prostate cancer cells. The observation that IL-8 mediates its growth and chemotactic effects via Src and FAK suggests the potential use for tyrosine kinase inhibitors at early stage of prostate cancer development.

Rights

Copyright © 2004 Nature Publishing. All rights reserved.

PubMed ID

14767470