Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo
Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo
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DOI：
10.1002/ijc.22528
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发表时间：
2007-05-15
影响因子：
6.4
通讯作者：
Kikkawa, Fumitaka
中科院分区：
文献类型：
--
作者：
Yamashita, Mamoru;Kajiyama, Hiroaki;Kikkawa, Fumitaka
氨肽酶N（APN/CD 13）是一种分子量为150 kDa的金属蛋白酶，是一种多功能的细胞表面氨肽酶，广泛表达于细胞表面。最近的研究表明，APN/CD 13在几种人类恶性肿瘤的肿瘤进展中起重要作用。在本研究中，我们研究了APN/CD 13在卵巢癌细胞（OVCA）紫杉醇（PAC）耐药中的作用。我们首先研究了APN/CD 13表达与PAC在各种OVCA细胞系中的IC 50值之间的相关性。接下来，我们研究了使用APN/CD 13活性抑制剂bestatin或siRNA技术抑制APN/CD 13是否会影响高表达APN/CD 13的ES-2细胞中的PAC敏感性。此外，我们使用裸鼠研究了bestatin对腹膜转移的影响。我们发现各种癌细胞系中APN/CD 13表达与对PAC的化疗敏感性之间呈负相关。随后，我们发现通过抑制这种酶，使用添加bestatin或ARNA技术，APN/CD 13表达OVCA细胞的PAC敏感性显著增加。此外，在使用裸鼠的腹膜转移模型中，与PAC单独治疗相比，PAC和bestatin的组合治疗引起存活时间的协同增加。(mean存活时间：分别为37.7 ± 7.0秒和27.1 ± 6.6天）。目前的研究结果表明，APN/CD 13可能参与了OVCA细胞对PAC敏感性的降低，这种作用的机制至少部分涉及其酶活性。APN/CD 13可能是OVCA联合化疗的治疗靶点。(c)2007 Wiley-Liss，Inc.
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 ARNA 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. (c) 2007 Wiley-Liss, Inc.