Recently, numerous studies have shown that
endothelin-1 (ET-1) is expressed in ovarian
carcinoma and that ET-1 selectively acts as an autocrine or paracrine
growth factor through the
endothelin A receptor (ET(A)R), and is involved in cell proliferation, invasiveness, neovascularization, and prevention of apoptosis.
Neutral endopeptidase 24.11 (NEP) is a cell surface
aminopeptidase with a ubiquitous expression and is capable of degrading a number of bioactive
peptides including ET-1. Our previous report showed that stromal NEP expression in ovarian
carcinoma was down-regulated as the histologic grade advanced. Here, we confirmed that NEP was expressed in
tumor cells as well as stromal tissues in ovarian
carcinoma, and investigated the functions of NEP in this
carcinoma. We showed that there was a significant decrease in cell proliferation and invasiveness with a reduction in the concentration of ET-1 in the
conditioned medium on the NEP overexpression of NEP in ovarian
carcinoma cells. In addition, the overexpression of NEP enhanced susceptibility to
paclitaxel, resulting in an increased occurrence of apoptotic morphologic change. Furthermore,
tumorigenesis was reduced in vivo with the overexpression of NEP, down-regulation of both
matrix metalloproteinase-2, and
vascular endothelial growth factor expression. This evidence suggests that NEP functionally suppresses the progression of ovarian
carcinoma and further study of this
enzyme may reveal an effective way to target ET-1 for the treatment of this
carcinoma.