P1-5-2 - Bradykinin Promotes Vascular Endothelial Growth Factor-Dependent Angiogenesis in Human Prostate Cancer

Abstract

Background: Prostate cancer is the most commonly diagnosed malignancy in men and shows a tendency for metastasis to distant organs. Angiogenesis is required for metastasis. Bradykinin (BK) is an inflammatory mediator involved in tumor growth and metastasis, but its role in vascular endothelial growth factor (VEGF) expression and angiogenesis in human prostate cancer remains unknown. The aim of this study was to examine whether BK promotes prostate cancer angiogenesis via VEGF expression.Methods: We knocked down bradykinin expression in human prostate cancer cells and assessed their capacity to control VEGF expression and angiogenesis. Signal transduction of bradykinin-mediated VEGF expression was evaluated by qPCR, ELISA, Western blot, and luciferace assay.Results: We found that exogenous bradykinin increased VEGF expression in prostate cancer cells and further promoted tube formation in endothelial progenitor cells and human umbilical vein endothelial cells. Pretreatment of prostate cancer with B2 receptor antagonist or small interfering RNA (siRNA) reduced bradykinin-mediated VEGF production. The Akt and mammalian target of rapamycin (mTOR) pathways were activated after bradykinin treatment, and bradykinin-induced VEGF expression was abolished by the specific inhibitor and siRNA of the Akt and mTOR cascades. bradykinin also promoted nuclear factor-kB (NF-kB) and activator protein 1 (AP-1) activity. Importantly, bradykinin knockdown reduced VEGF expression and abolished prostate cancer cell conditional medium-mediated angiogenesis.Conclusions: Our results demonstrate that bradykinin operates through the B2 receptor, Akt, and mTOR, which in turn activate NF-kB and AP-1, activating VEGF expression and contributing to angiogenesis in human prostate cancer.