Expression of Smac/DIABLO in ovarian carcinoma cells induces apoptosis via a caspase-9-mediated pathway

被引:89
作者
McNeish, IA [1 ]
Bell, S [1 ]
McKay, T [1 ]
Tenev, T [1 ]
Marani, M [1 ]
Lemoine, NR [1 ]
机构
[1] Hammersmith Hosp, Imperial Coll Sch Med, Canc Res UK Mol Oncol Unit, London W12 0NN, England
关键词
Smac/DIABLO; ovarian cancer; adenovirus; caspase; cisplatin; ENDOPLASMIC-RETICULUM STRESS; DEPENDENT CASPASE ACTIVATION; CYTOCHROME-C RELEASE; X-LINKED INHIBITOR; SERINE-PROTEASE; DEATH PROGRAM; BCL-2; FAMILY; MITOCHONDRIA; BINDING; SMAC;
D O I
10.1016/S0014-4827(03)00073-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We have constructed Ad CMV-Smac, a recombinant adenovirus encoding Smac/DIABLO, the recently described second mitochondrial activator of caspases. Transfection of ovarian carcinoma cells with Ad CMV-Smac at multiplicities of infection of 3-60 pfu/cell leads to increasing apoptosis in a dose-dependent manner. Western blot analysis confirms that Smac-induced apoptosis proceeds via a pathway mediated primarily by caspase-9 that can be inhibited by zLEHD-fmk and overexpression of the X-linked inhibitor of apoptosis protein (XIAP). In contrast, there is no cleavage of either caspase-8 or caspase-12. Ad CMV-Smac appears to induce apoptosis independently of cytochrome c release from mitochondria and is not inhibited by overexpression of Bcl-2. Ad CMV-Smac can combine with other proapoptotic factors, such as cisplatin, paclitaxel, and procaspase-3, to produce greater levels of apoptosis in transfected cells. (C) 2003 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:186 / 198
页数:13
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