DNA连接酶IV作为替莫唑胺的新分子靶点。
DNA ligase IV as a new molecular target for temozolomide.
作者信息
Kondo Natsuko, Takahashi Akihisa, Mori Eiichiro, Ohnishi Ken, McKinnon Peter J, Sakaki Toshisuke, Nakase Hiroyuki, Ohnishi Takeo
机构信息
Department of Biology, Nara Medical University, Shijo-cho, Kashihara, Japan.
出版信息
Biochem Biophys Res Commun. 2009 Oct 2;387(4):656-60. doi: 10.1016/j.bbrc.2009.07.045. Epub 2009 Jul 15.
Abstract
Temozolomide (TMZ) is a methylating agent used in chemotherapy against glioblastoma. This work was designed to clarify details in repair pathways acting to remove DNA double-strand breaks (DSBs) induced by TMZ. Cultured mouse embryonic fibroblasts were used which were deficient in DSB repair genes such as homologous recombination repair-related genes X-ray repair cross-complementing group 2 (XRCC2)and radiation sensitive mutant54 (Rad54), non-homologous end joining repair-related gene DNAligase IV (Lig4). Cell sensitivity to drug treatments was assessed using colony forming assays. The most effective molecular target which was correlated with TMZ cell sensitivity was Lig4. In addition, it was found that small interference RNAs (siRNA) for Lig4 efficiently enhanced cell lethality induced by TMZ in human glioblastoma A172 cells. These findings suggest that down regulation of Lig4 might provide a useful tool for cell sensitization during TMZ chemotherapy.
摘要
替莫唑胺（TMZ）是一种用于化疗治疗胶质母细胞瘤的甲基化剂。这项工作旨在阐明在修复由TMZ诱导的DNA双链断裂（DSB）的途径中的细节。使用了培养的小鼠胚胎成纤维细胞，这些细胞缺乏DSB修复基因，如同源重组修复相关基因X射线修复交叉互补组2（XRCC2）和辐射敏感突变体54（Rad54），以及非同源末端连接修复相关基因DNA连接酶IV（Lig4）。使用集落形成试验评估细胞对药物治疗的敏感性。与TMZ细胞敏感性相关的最有效的分子靶点是Lig4。此外，还发现针对Lig4的小干扰RNA（siRNA）可有效增强TMZ在人胶质母细胞瘤A172细胞中诱导的细胞杀伤力。这些发现表明，Lig4的下调可能为TMZ化疗期间的细胞致敏提供一种有用的工具。
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