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

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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.

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Acknowledgements

The work was supported by NIH grants (CA39207, DK52695, CA 57179 and CA82073 to H J K, K08 DK60748 to CPE and P30 CA93373 to UC Davis Cancer Center) and DOD DAMD 17-02-1-0020 to HJK. L.F. L. acknowledges the support of a DOD prostate cancer postdoctoral fellowship, and ML is supported by an NIH MCB training grant to UC Davis.

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  1. Li-Fen Lee and Maggie C Louie: These two authors contribute equally.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Stanford University, School of medicine, Stanford, 94305, CA, USA

    Li-Fen Lee

  2. Department of Biological Chemistry and Cancer Center, University of California at Davis, Sacramento, 95817, CA, USA

    Maggie C Louie, Sonal J Desai, Hong-Wu Chen & Hsing-Jien Kung

  3. Department of Urology, University of California at Davis, Sacramento, 95817, CA, USA

    Joy Yang & Christopher P Evans

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  1. Li-Fen Lee
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Correspondence to Hsing-Jien Kung.

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Lee, LF., Louie, M., Desai, S. et al. Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK. Oncogene 23, 2197–2205 (2004). https://doi.org/10.1038/sj.onc.1207344

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  • DOI: https://doi.org/10.1038/sj.onc.1207344

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