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Horiguchi A , Chen DYT , Goodman OB , Zheng R , Shen R , Guan H , Hersh LB , Nanus DM
Neutral endopeptidase inhibits prostate cancer tumorigenesis by reducing FGF-2-mediated angiogenesis
Prostate Cancer and Prostatic Diseases. 2008 Mar;11(1) :79-87
AbstractNeutral endopeptidase ( NEP) is a cell surface peptidase that catalytically inactivates a variety of physiologically active peptides including basic fibroblast growth factor ( FGF-2). We investigated the effect of using lentivirus to overexpress NEP in NEP-deficient DU145 prostate cancer cells. Third-generation lentiviral vectors encoding wild-type NEP ( L-NEP), catalytically inactive mutant NEP ( L-NEPmu), and green fluorescent protein ( L-GFP) were stably introduced into DU145 cells. FGF-2 levels in cell culture supernatants decreased by 80% in L-NEP-infected DU145 cells compared to cells infected with L-NEPmu or L-GFP ( P<0.05) while levels of other angiogenic factors were not altered. In vitro tubulogenesis of human vascular endothelial cells induced by conditioned media from DU145 cells infected with L- NEP was significantly reduced compared with that from DU145 cells infected with L-GFP ( P<0.05). Tumor xenografts from L-NEP-infected DU145 cells were significantly smaller compared to control cell xenografts and vascularity within these tumors was decreased ( P<0.05). Our data suggest that stable expression of NEP in DU145 cells inhibits prostate cancer tumorigenicity by inhibiting angiogenesis, with a probable mechanism being proteolytic inactivation of FGF-2.
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