Neutral Endopeptidase 24.11/CD10 Suppresses Progressive Potential in Ovarian Carcinoma In vitro and In vivo

Abstract

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 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.

Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase

“…We and others have shown that the neuropeptides bombesin and ET-1 stimulate PC cell migration and invasion (Aprikian et al, 1997;Shen et al, 2000;Kajiyama et al, 2005). Here, we have demonstrated that (i) bombesin and ET-1 stimulate RhoA activation and stress fiber formation; (ii) NEP proteolytically inhibits bombesin and ET-1-stimulated RhoA activation; (iii) Ga 13 and the RhoA effector, ROCK, are required for bombesin-and ET-1-stimulated PC cell migration; (iv) FAK is required for bombesinstimulated RhoA activation; and (v) PDZ-RhoGEF and LARG link bombesin receptors to RhoA.…”

Fukutin, identified by the Escherichia coli ampicillin secretion trap (CAST) method, participates in tumor progression in gastric cancer

“…Moreover, prostate-specific antigen recurrence was significantly associated with the staining pattern and subcellular localization of CD10 [33]. In contrast, in ovarian cancer, overexpression of CD10 enhanced susceptibility to paclitaxel, resulting in an increased occurrence of apoptosis, as well as downregulation of both matrix metalloproteinase 2 and vascular endothelial growth factor expression [34]. In colorectal cancer, CD10 expression is associated with colorectal cancer metastases, especially liver metastasis [35].…”

Expression of Twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients

“…Once EOC cells adhere to mesothelial cells, the tumour cells may gradually migrate through the layers of these cells, invade the local region and spread to distant organs (Coukos and Rubin, 1998;Sood and Buller, 1998;Lessan et al, 1999). In this multisteps metastasis, tumour cells proceed from a noninvasive to an invasive, malignant phenotype (Kajiyama et al, 2002(Kajiyama et al, , 2005. During this process, the morphology of the tumour cells changes from an epithelioid or cobblestone appearance to a fibroblastic form through a process referred to as epithelial -mesenchymal transition (EMT) (Boyer et al, 2000;Savagner, 2001;Vernon and LaBonne, 2004).…”