Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer.
Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer.
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DOI：
10.1038/sj.onc.1210977
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发表时间：
2008-05-15
期刊：
影响因子：
8
通讯作者：
McNeish, I. A.
中科院分区：
文献类型：
--
作者：
Baird, S. K.;Aerts, J. L.;Eddaoudi, A.;Lockley, M.;Lemoine, N. R.;McNeish, I. A.
溶瘤腺病毒突变体在卵巢癌中具有相当大的活性。然而，它们诱导细胞死亡的机制仍不确定。dl922-947在E1A CR2中含有24bp的缺失，比E1A野生型腺病毒和E1B-55K缺失突变体dl1520 （Onyx-015）更有效。我们研究了三种E1A cr2缺失复制腺病毒在卵巢癌模型中诱导的死亡模式，以及E3 11.6（腺病毒死亡蛋白）在决定这种死亡模式中的重要性。用dl922-947 （E3 11.6+）和dlCR2 （E3 11.6−）分别感染卵巢癌细胞。我们还生成了dlCR2 tmac，它也编码处理过的Smac/DIABLO基因。典型的细胞凋亡不发生在腺病毒细胞死亡中，线粒体也没有作用。表达Smac/DIABLO不增强细胞毒性，也不增加凋亡特征。排除了组织蛋白酶和溶酶体膜通透性的作用。自噬是诱导的，但不是死亡的方式，可能作为一种细胞存活机制。没有纯粹坏死的证据，而E3 11.6的存在并不调节细胞死亡的方式或程度。因此，卵巢癌中E1A cr2缺失的溶瘤腺病毒细胞毒性可能定义了一种新的程序性细胞死亡模式。
Oncolytic adenoviral mutants have considerable activity in ovarian cancer. However, the mechanisms by which they induce cell death remain uncertain. dl922-947, which contains a 24 bp deletion in E1A CR2, is more potent than both E1A wild-type adenoviruses and the E1B-55K deletion mutant dl1520 (Onyx-015). We investigated the mode of death induced by three E1A CR2-deleted replicating adenoviruses in models of ovarian cancer and also the importance of E3 11.6 (adenovirus death protein) in determining this mode of death. Ovarian cancer cells were infected with dl922-947 (E3 11.6+) and dlCR2 (E3 11.6−). We also generated dlCR2 tSmac, which also encodes the gene for processed Smac/DIABLO. Classical apoptosis does not occur in adenoviral cell death and there is no role for mitochondria. Expression of Smac/DIABLO does not enhance cytotoxicity nor increase apoptotic features. A role for cathepsins and lysosomal membrane permeability was excluded. Autophagy is induced, but is not the mode of death and may act as a cell survival mechanism. There is no evidence of pure necrosis, while the presence of E3 11.6 does not modulate the mode or extent of cell death. Thus, E1A CR2-deleted oncolytic adenoviral cytotoxicity in ovarian cancer may define a novel mode of programmed cell death.
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