A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells
A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells
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DOI：
10.1002/ijc.21509
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发表时间：
2006-03-15
影响因子：
6.4
通讯作者：
Kikkawa, F
中科院分区：
文献类型：
--
作者：
Kondo, C;Shibata, K;Kikkawa, F
在最近的几项研究中，我们已经证明P-LAP在子宫内膜癌中可能是一个不良的预后因素和化疗耐药因素，特别是在晚期患者中。在我们的研究中，我们研究了P-LAP是否改变了凋亡调节蛋白的表达，作为耐药的一个机制。将P-LAP基因导入子宫内膜腺癌细胞系A-MEC，A-MEC-LAP细胞对紫杉醇、卡铂和顺铂的IC50分别增加1.8倍、2.0倍和1.7倍。在A-MEC-LAP细胞上，siRNA2对P-LAP的翻译下调显示IC50分别降低了60%、51%和58%。为了探讨PLAP诱导化疗耐药的机制，我们还观察了P-LAP基因对卡铂诱导的A-MEC细胞凋亡的影响。A-MEC和A-MEC-PC(单独转染卡铂)细胞对卡铂有较强的凋亡反应，而A-MEC-LAP细胞表现出较弱的凋亡反应。为了确定卡铂抑制细胞凋亡反应的机制，我们接下来研究了裂解的caspase和PARP裂解的表达。经卡铂处理的AMEC-PC细胞中caspase3、caspase7和caspase9的裂解水平明显高于未处理的AMEC-PC细胞，而A-MEC-LAP细胞不表达这些caspase3、caspase7和caspase 9。这些结果表明，P-LAP通过抑制线粒体介导的细胞凋亡来降低对抗癌药物的敏感性，可能是克服抗癌药物耐药性的分子靶点。(C)2005年Wiley-Liss，Inc.
In several recent studies, we have shown that P-LAP can be a poor prognostic factor and a factor of chemoresistance in endometrial carcinoma, especially in the advanced patients. In our study, we investigated whether P-LAP alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We transfected P-LAP cDNA into A-MEC cells (endometrial adenocarcinoma cell line), and A-MEC-LAP cells displayed a 1.8-fold, 2.0-fold and 1.7-fold increase in IC50 against paclitaxel, carboplatin and cisplatin respectively. Translational downregulation by siRNA2 to P-LAP on A-MEC-LAP cells demonstrated 60%, 51% and 58% decrease in IC50. To investigate the mechanism of PLAP-induced chemoresistance, we also assessed whether P-LAP transfection had an effect on carboplatin-induced apoptotic death of A-MEC cells. A-MEC and A-MEC-pc (transfected with vector alone) cells exhibited a strong apoptotic response to carboplatin, while A-MEC-LAP cells exhibited a weak apoptotic response. In an attempt to identify the mechanism of the inhibitory effect on apoptotic response to carboplatin, we next assessed the expression of cleaved caspases and PARP cleavage. While treatment of AMEC-pc cells with carboplatin exhibited increased levels of cleaved caspase 3, caspase 7 and caspase 9 compared to that after no treatment, A-MEC-LAP cells did not show any expression of these caspases. These results suggest that P-LAP reduces sensitivity to anticancer drugs via inhibition of mitochondria-mediated apoptosis, and may be a molecular target for conquering anticancer drug resistance. (c) 2005 Wiley-Liss, Inc.