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

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.