Inhibition of APN/CD13 leads to suppressed progressive potential in ovarian carcinoma cells

Mikio Terauchi,Fumitaka Kikkawa,Hiroaki Kajiyama,Kazuhiko Ino,Akihiro Nawa,Kiyosumi Shibata,Shigehiko Mizutani

doi:10.1186/1471-2407-7-140

Abstract

BackgroundAminopeptidase N (APN/CD13), a 150-kDa metalloprotease, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression of several human malignancies. In the current study, we investigated the role of APN/CD13 in ovarian carcinoma (OVCA) progression.MethodsWe first examined the expression of APN/CD13 at the protein level in a variety of OVCA cell lines and tissues. We subsequently investigated whether there was a correlation between APN/CD13 expression and invasive potential of various OVCA cell lines. Moreover, we investigated the function of APN/CD13 in OVCA cells using bestatin, an APN/CD13 inhibitor, or transfection of siRNA for APN/CD13.ResultsWe confirmed that APN/CD13 was expressed in OVCA tissues and cell lines to various extents. There was a positive correlation between APN/CD13 expression and migratory potential in various OVCA cell lines with accordingly enhanced secretion of endogenous MMP-2. Subsequently, we found a significant decrease in the proliferative and migratory abilities of OVCA cells after the addition of bestatin or the inhibition of APN/CD13 expression by siRNA. Furthermore, in an animal model, daily intraperitoneal administration of bestatin after inoculation of OVCA cells resulted in a decrease of peritoneal dissemination and in prolonged survival of nude mice.ConclusionThe current data indicate the possible involvement of APN/CD13 in the development of OVCA, and suggest that clinical use of bestatin may contribute to better prognosis for ovarian carcinoma patients.

Highlights

Aminopeptidase N (APN/CD13), a 150-kDa metalloprotease, is a multifunctional cell surface aminopeptidase with ubiquitous expression
We found a small number of APN/CD13-positive blood vessels in all ovarian carcinoma (OVCA) tissues the vascular density did not seem to be associated with the APN/CD13 expression in the tumor cells
SKOV-3, ES-2 and HEY cells were intensely positive for APN/CD13, while in other cell lines, the level of APN/ CD13 expression was lower, which was consistent with data obtained by enzyme activity analysis

Summary

Introduction

Aminopeptidase N (APN/CD13), a 150-kDa metalloprotease, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/ CD13 plays an important role in tumor progression of several human malignancies. We investigated the role of APN/CD13 in ovarian carcinoma (OVCA) progression. APN is a cell surface aminopeptidase that was originally characterized as a myeloid (page number not for citation purposes). APN/CD13 activates or inactivates bioactive peptides on the cell surface by cleaving them enzymatically and regulates their availability to adjacent cells. A number of studies have provided evidence that APN/CD13 may play a role in tumor progression by regulating processes such as cell-cell contact, proliferation, tumor invasion, and angiogenesis [5,10,11,12,13,14]. A recent study showed that APN/CD13 was involved in the protection of leukemic cells against apoptosis[15]

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