Inhibition of DNA repair by a herpes simplex virus vector enhances the radiosensitivity of human glioblastoma cells
Inhibition of DNA repair by a herpes simplex virus vector enhances the radiosensitivity of human glioblastoma cells
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DOI：
10.1158/0008-5472.can-04-3793
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
DeLuca, NA
中科院分区：
文献类型：
--
作者：
Hadjipanayis, CG;DeLuca, NA
单纯疱疹病毒(HSV)蛋白ICP0从病毒基因组中表达，使两个抗辐射的人多形性胶质母细胞瘤细胞系对电离辐射更敏感。用3-(4，5-dimethylthiazol-2-yl)2，5-diphenyltetrazolium溴化法和克隆形成法检测，与不表达ICP0相比，预表达ICP0的U87-MG和T98细胞的存活率随电离辐射剂量的增加而显著降低。与以前的结果一致，我们发现DNA依赖的蛋白激酶催化亚单位在两种类型的细胞中都随着ICP0的作用而降解。这很可能导致了DNA修复的抑制，这是由伽马H_2AX焦点或DNA双链断裂的持久性所推断的。用产生ICP0的HSV-1突变体d106预先感染U87-MG细胞后，也发现细胞凋亡增强。我们的结果提示ICP0在人多形性胶质母细胞瘤细胞中的表达抑制了电离辐射治疗后DNA双链断裂的修复，部分通过诱导细胞凋亡来降低细胞的存活率。
Expression of the herpes simplex virus (HSV) protein, ICP0, from the viral genome, rendered two radioresistant human glioblastoma multiforme cell lines more sensitive to the effects of ionizing radiation. Using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide and clonogenic survival assays, U87-MG and T98 cell survival was more great decreased as a function of ionizing radiation dose when ICP0 was preexpressed in cells compared with when ICP0 was not expressed. Consistent with previous results, we found that the catalytic subunit of DNA-dependent protein kinase was degraded as a function of ICP0 in both cell types. This most likely resulted in the inhibition of DNA repair as inferred by the persistence of gamma H2AX foci or DNA double-strand breaks. Enhanced apoptosis was also found to occur following irradiation of U87-MG cells preinfected with the ICP0-producing HSV-1 mutant, d106. Our results suggest that expression of ICP0 in human glioblastoma multiforme cells inhibits the repair of DNA double-strand breaks after ionizing radiation treatment, decreasing the survival of these cells in part by induction of apoptosis.