Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo
Article first published online: 31 JAN 2007
Copyright © 2007 Wiley-Liss, Inc.
International Journal of Cancer
Volume 120, Issue 10, pages 2243–2250, 15 May 2007
How to Cite
Yamashita, M., Kajiyama, H., Terauchi, M., Shibata, K., Ino, K., Nawa, A., Mizutani, S. and Kikkawa, F. (2007), Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo. Int. J. Cancer, 120: 2243–2250. doi: 10.1002/ijc.22528
- Issue published online: 23 MAR 2007
- Article first published online: 31 JAN 2007
- Manuscript Accepted: 17 NOV 2006
- Manuscript Received: 27 JUN 2006
- paclitaxel (PAC);
- ovarian carcinoma (OVCA)
Aminopeptidase N (APN/CD13), a 150-kDa metalloproteinase, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression in several human malignancies. In the current study, we investigated the role of APN/CD13 in paclitaxel (PAC)-resistance of ovarian carcinoma (OVCA) cells. We first examined the correlation between APN/CD13 expression and IC50 values of PAC in a variety of OVCA cell lines. Next we investigated whether suppression of APN/CD13 using bestatin, an inhibitor of APN/CD13 activity or the siRNA technique influenced PAC-sensitivity in ES-2 cells, which highly express APN/CD13. Moreover, we investigated the effect of bestatin on peritoneal metastasis using nude mice. We found a negative correlation between APN/CD13 expression and chemosensitivity to PAC in various carcinoma cell lines. Subsequently, we found a significant increase in PAC-sensitivity of APN/CD13 expressing OVCA cells by suppression of this enzyme, using the addition of bestatin or the siRNA technique. Furthermore, in a peritoneal metastasis model using nude mice, combination treatment with PAC and bestatin caused a synergistic increase of survival time compared with PAC alone treatment. (mean survival time: 37.7 ± 7.0 s and 27.1 ± 6.6 days, respectively). The present findings showed that APN/CD13 may be involved in decreased sensitivity to PAC in OVCA cells and that the mechanism of this effect involves its enzyme activity at least in part. APN/CD13 may be a therapeutic target for the treatment of OVCA in combination with chemotherapy. © 2007 Wiley-Liss, Inc.