Direct gene transfer of adenoviral-mediated interferon α into human bladder cancer cells but not the bystander factors produced induces endoplasmic reticulum stress-related cytotoxicity.
Direct gene transfer of adenoviral-mediated interferon α into human bladder cancer cells but not the bystander factors produced induces endoplasmic reticulum stress-related cytotoxicity.
复制标题
将腺病毒介导的干扰素α直接转移到人膀胱癌细胞中，但旁观者因子产生的因子诱导了内质网应激相关的细胞毒性。
DOI：
10.1038/cgt.2010.76
复制
发表时间：
2011-04
期刊：
影响因子：
5.1
通讯作者：
Benedict, W. F.
中科院分区：
文献类型：
--
作者：
Zhang, X-Q;Yang, Z.;Benedict, W. F.
我们之前已经证明腺病毒介导的干扰素α (Ad-IFNα)对重组干扰素（IFNα）敏感的细胞和对IFNα耐药的细胞都具有细胞毒性。Ad-IFNα的癌细胞特异性细胞毒作用涉及三种不同的机制：1。IFNα产生对IFNα敏感细胞杀伤的直接作用2. Ad-IFNα感染和IFNα高水平表达在IFNα耐药癌细胞中的直接作用和3。间接作用是由ad - ifn - α旁观者因子产生的。Ad-IFNα感染后，细胞产生大量核周定位的IFN蛋白。与产生间接细胞毒性作用的旁观者因素相比，这种蛋白质超载可能是直接杀死被Ad-IFNα感染的细胞的主要因素。在这里，我们研究了ad- ifn诱导的细胞死亡的一个组成部分是否涉及蛋白质过载诱导的内质网（ER）应激，使用ifn α-耐药的人膀胱癌细胞系（KU7）和正常的人尿路上皮细胞系TERT-NHUC作为临床前模型。我们发现两条内质网应激反应通路在KU7细胞中被激活。相反，用Ad-IFNα处理正常TERT-NHUC细胞后，未观察到内质网应激信号。此外，当KU7细胞暴露于Ad-IFNα处理的KU7细胞的条件培养基中时，没有发现内质网应激相关的变化，这表明旁观者产生的细胞毒性与内质网应激无关。Ad-IFNα感染24小时后，KU7癌细胞产生剪接的X-box结合蛋白1 （sXBP1）和激活转录因子6蛋白（ATF6），引起内质网应激反应，可能有助于Ad-IFNα诱导这些癌细胞凋亡。此外，GADD153/CHOP、GADD34和BAX在内质网应激通路激活后也随之被修饰，从而以促凋亡的方式向下游效应物发出信号。
We have previously shown that adenoviral-mediated interferon α (Ad-IFNα) is cytotoxic both to cells that are sensitive to recombinant interferon (IFNα) and to cells which are resistant to IFNα. The cancer cell-specific cytotoxic effects of Ad-IFNα involve three different mechanisms: 1. The direct effect of IFNα production causing cancer cell kill in IFNα sensitive cells; 2. The direct effect of Ad-IFNα infection and high levels of IFNα expression in IFNα resistant cancer cells; and 3. The indirect effect of the Ad-IFNα bystander factors produced. After Ad-IFNα infection, the cells produce a large amount of perinuclear localized IFN protein. This protein over-load could be a major factor in the direct cancer cell kill of those cells infected with Ad-IFNα compared to the indirect cytotoxic effects of the bystander factors produced. Here we investigated whether a component of Ad-IFN-induced cell death involves protein overload-induced endoplasmic reticular (ER) stress, using an IFNα-resistant human bladder cancer cell line (KU7), and the normal human urothelial cell line, TERT-NHUC, as preclinical models. We found that two ER stress response pathways examined were activated in KU7 cells. In contrast, following treatment of the normal TERT-NHUC cells with Ad-IFNα no ER stress signals were observed. In addition, no ER stress related changes were seen when KU7 cells were exposed to conditioned medium from Ad-IFNα treated KU7 cells indicating that bystander produced cytotoxicity did not involve ER stress. After 24hr of Ad-IFNα infection, the KU7 cancer cells produced spliced X-box binding protein 1 (sXBP1) and activating transcription factor 6 protein (ATF6), evoking an ER stress response that could contribute to Ad-IFNα induced apoptosis in these cancer cells. In addition, GADD153/CHOP, GADD34 and BAX were also subsequently modified following activation of the ER stress pathways, thereby signaling downstream effectors in a pro-apoptotic manner.
登录
查看更多内容
影响因子：
6.4
作者：
通讯作者：
--
影响因子：
6.4
作者：
Zhang, X.;Dong, L.;Benedict, W. F.
通讯作者：
Benedict, W. F.
影响因子：
11.2
作者：
Papageorgiou, A;Lashinger, L;McConkey, DJ
通讯作者：
McConkey, DJ
影响因子：
12.4
作者：
Benedict, WF;Tao, ZM;Connor, RJ
通讯作者：
Connor, RJ
影响因子：
6.4
作者：
Zhang, X.;Yang, Z.;Benedict, W. F.
通讯作者：
Benedict, W. F.