New strategy for gynecologic cancer targeting of membrane-bound protease

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In the present study, we examined the involvement of membrane-bound aminopeptidase in the inhibitory or progressive effect of uterine and ovarian cancer aiming for new therapeutic strategy. We focused on APN/CD13, DPPIV/CD26, IRAP/PLAP, NEP/CD10, and APA as aminopeptidases. Our current findings are as follows. 1) In ovarian cancer cells, DPPIV/CD26 and NEP/CD10 induced the decreased invasiveness, enhanced sensitivity to paclitaxel, and decreased formation of peritoneal metastasis using a mouse-dissemination model. 2) In addition, DPPIV/CD26 induced mesenchymal-epithelial transition (MET) in ovarian cancer cells. 3) As the mechanisms, these aminopeptidases enzymatically degraded SDF-la or Endothelin, which stimulated metastasis and the resistance to anti-neoplastic agents in ovarian cancer. 4) Conversely, the expression of APN/CD13 induced cell-invasiveness and the resistance to paclitaxel in ovarian cancer. Moreover, the inhibition of APN/CD13 using bestatin or siRNA technique resulted in upregulation of sensitivity to paclitaxel and decreased peritoneal metastasis in animal model. 5) Similarly, in uterine cervical cancer cells, the expression of APN/CD13 was involved in enhanced metastatic potential during irradiation and the treatment with bestatin reversed this effect. 6) In uterine endometrial cancer cells, the expression of IRAP/PLAP was involved in the resistance to carboplatin or paclitaxel, and the siRNA specific for IRAP/PLAP reversed the chemosensitivities to these agents. 7) In ovarian cancer, angiotensin-II plays a crucial role in the angiogenesis and the formation of peritoneal dissemination via ATR1. We found that the treatment with an antagonist specific for ATR1 reverse these effects suggesting that it may be useful as a new therapeutic agent.