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Cell, Tumor, and Stem Cell Biology |
Departments of 1 Urology, 2 Cell Biology and Anatomy, 3 Radiation Oncology, and 4 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
Requests for reprints: Bal L. Lokeshwar, Department of Urology (M-800), School of Medicine, University of Miami, P.O. Box 016960, Miami, FL 33101. Phone: 305-243-1012; Fax: 305-243-9724; E-mail: blokeshw{at}miami.edu.
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/106 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 (>3.5x) 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 2- to 3-fold reduction in PSA and AR levels, when compared with vector transfectants. IL8-S cells expressed 2- to 3-fold higher levels of phospho-EGFR, src, Akt, and nuclear factor
B (NF-
B) and showed increased survival when treated with docetaxel. This increase was blocked by NF-
B and src inhibitors, but not by an Akt inhibitor. IL8-S transfectants displayed a 3- to 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 androgen-independent prostate cancer growth and progression. [Cancer Res 2007;67(14):6854–62]
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