Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection
Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection
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DOI：
10.1038/sj.onc.1204842
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发表时间：
2001-10-18
期刊：
影响因子：
8
通讯作者：
Tyler, KL
中科院分区：
文献类型：
--
作者：
Clarke, P;Meintzer, SM;Tyler, KL
TRAIL(肿瘤坏死因子相关的凋亡诱导配体)通过与死亡受体4(DR4)和5(DR5)结合来诱导易感细胞的凋亡。TRAIL优先诱导转化细胞的凋亡，识别TRAIL诱导的细胞凋亡的机制可能会导致新的肿瘤化疗策略。在这里，我们展示了呼肠孤病毒感染诱导来自人类乳腺癌、肺癌和宫颈癌的癌细胞系的凋亡。呼肠孤病毒诱导的细胞凋亡是由TRAIL介导的，并与感染细胞释放TRAIL有关。呼肠孤病毒感染协同并特异性地使癌细胞对外源TRAIL的杀伤敏感。这种敏化既提高了先前耐药细胞系对TRAIL诱导的细胞凋亡的敏感性，又减少了杀死已经敏感的细胞系所需的TRAIL数量。致敏与TRAIL表达的可检测变化无关。呼肠孤病毒感染细胞中的受体。致敏作用与死亡受体相关启动子caspase活性的增加有关。Caspase 8，并被IETD-fmk抑制，表明呼肠孤病毒以caspase 8依赖的方式使癌细胞对TRAIL诱导的细胞凋亡敏感。呼肠孤病毒诱导的细胞对TRAIL的敏感性也与PARP的切割增加有关，PARP是效应器caspase3和7的底物。
TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in susceptible cells by binding to death receptors 4 (DR4) and 5 (DR5). TRAIL preferentially induces apoptosis in transformed cells and the identification of mechanisms by which TRAIL-induced apoptosis can be enhanced may lead to novel cancer chemotherapeutic strategies. Here we show that reovirus infection induces apoptosis in cancer cell lines derived from human breast, lung and cervical cancers. Reovirus-induced apoptosis is mediated by TRAIL and is associated with the release of TRAIL from infected cells. Reovirus infection synergistically and specifically sensitizes cancer cell lines to killing by exogenous TRAIL. This sensitization both enhances the susceptibility of previously resistant cell lines to TRAIL-induced apoptosis and reduces the amount of TRAIL needed to kill already sensitive lines. Sensitization is not associated with a detectable change in the expression of TRAIL. receptors in reovirus-infected cells. Sensitization is associated with an increase in the activity of the death receptor-associated initiator caspase. caspase 8, and is inhibited by the peptide IETD-fmk, suggesting that reovirus sensitizes cancer cells to TRAIL-induced apoptosis in a caspase 8-dependent manner. Reovirus-induced sensitization of cells to TRAIL is also associated with increased cleavage of PARP, a substrate of the effector caspases 3 and 7.