Independence and Progression in Prostate Cancer Interleukin-8 Is a Molecular Determinant of Androgen

The proinflammatory chemokine interleukin-8 (IL-8) is undetectable in androgen-responsive prostate cancer cells (e.g., LNCaP and LAPC-4), but it is highly expressed in androgen-independent metastatic cells, such as PC-3. In this report, we show IL-8 functions in androgen independence, chemoresistance, tumor growth, and angiogenesis. We stably transfected LNCaP and LAPC-4 cells with IL-8 cDNA and selected IL-8–secreting (IL8-S) transfectants. The IL8-S transfectants that secreted IL-8 at levels similar to that secreted by PC-3 cells (100–170 ng/10 cells) were characterized. Continuous or transient exposure of LNCaP and LAPC-4 cells to IL-8 reduced their dependence on androgen for growth and decreased sensitivity (>3.5 ) to an antiandrogen. IL-8– induced cell proliferation was mediated through CXCR1 and was independent of androgen receptor (AR). Quantitative PCR, immunoblotting, and transfection studies showed that IL8-S cells or IL-8–treated LAPC-4 cells exhibit a 2to 3-fold reduction in PSA and AR levels, when compared with vector transfectants. IL8-S cells expressed 2to 3-fold higher levels of phospho-EGFR, src, Akt, and nuclear factor KB (NF-KB) and showed increased survival when treated with docetaxel. This increase was blocked by NF-KB and src inhibitors, but not by an Akt inhibitor. IL8-S transfectants displayed a 3to 5-fold increased motility, invasion, matrix metalloproteinase-9 and vascular endothelial growth factor production. LNCaP IL8-S cells grew rapidly as tumors, with increased microvessel density and abnormal tumor vasculature when compared with the tumors derived from their vector-transfected counterparts. Therefore, IL-8 is a molecular determinant of androgenindependent prostate cancer growth and progression. [Cancer Res 2007;67(14):6854–62]