Interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) are two cytokines promoting prostate tumor growth and angiogenesis. The main coagulation protease thrombin may modulate the malignant phenotype of prostate cancer cells via its cellular receptor(s). We aimed to investigate the effects of thrombin on IL-8 and VEGF expression in DU 145 prostate cancer cells. Thrombin induced the expression and secretion of IL-8 and VEGF, with more pronounced effects on IL-8. Target-specific siRNA-induced protease-activated receptor I (PAR-1) knockdown completely neutralized thrombin-enhanced cytokine secretion, demonstrating the essential role of PAR-1. Inhibitors of either extracellular signal-regulating kinase (ERK) or phosphatidylinositol 3-kinase (PI3K) partly reversed the thrombin-induced cytokine expression, suggesting that both ERK and PI3K kinase pathways may be involved in IL-8 and VEGF expression. The results suggest that the thrombin/PAR-1 system upregulates cytokines in prostate cancer cells which in turn may contribute to the progression of prostate cancer. (c) 2006 Elsevier Inc. All rights reserved.