Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair.
Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair.
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通过敲低 DNA-PKcs 或 NU7441 使 DNA-PK 失活会损害辐射诱导的双链断裂修复的非同源末端连接。
DOI：
10.3892/or.2018.6217
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发表时间：
2018-03
期刊：
影响因子：
4.2
通讯作者：
Wen B
中科院分区：
文献类型：
--
作者：
Dong J;Ren Y;Zhang T;Wang Z;Ling CC;Li GC;He F;Wang C;Wen B
DNA依赖蛋白激酶(DNA-PK)复合体在非同源末端连接(NHEJ)修复中起着关键作用。我们研究了高选择性DNA-PK抑制剂NU7441在NHEJ耐受的小鼠胚胎成纤维细胞(MEF)和NHEJ缺陷细胞中的作用机制，并探讨了其用于鼻咽癌(NPC)细胞放射增敏的可行性。我们建立了野生型和DNA-PKcs−/−MEF细胞。采用克隆存活实验、流式细胞仪和免疫印迹等方法研究NU7441对细胞存活、细胞周期和DNA修复的影响。NU7441对野生型MEF细胞和SUNE-1细胞有明显的辐射增敏作用，但对DNA-PKcs−/−MEF细胞无辐射增敏作用。NU7441可显著抑制辐射诱导的DSB修复，通过未修复和致死性DNA损伤，使细胞周期停滞。这种作用与细胞周期检查点的激活有关。本研究揭示了抑制DNA-PK使细胞对辐射增敏的机制，提示放疗联合DNA-PK抑制剂是治疗鼻咽癌的一种有前途的范例，值得进一步研究。
The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosensitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs−/− MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair. NU7441 profoundly radiosensitized wild-type MEF cells and SUNE-1 cells, but not DNA-PKcs−/− MEF cells. NU7441 significantly suppressed radiation-induced DSB repair post-irradiation through unrepaired and lethal DNA damage, the cell cycle arrest. The effect was associated with the activation of cell cycle checkpoints. The present study revealed a mechanism by which inhibition of DNA-PK sensitizes cells to irradiation suggesting that radiotherapy in combination with DNA-PK inhibitor is a promising paradigm for the management of NPC which merits further investigation.
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影响因子：
2.9
作者：
Lu, Qiu-Ping;Chen, Wen-Dan;Guan, Zhong
通讯作者：
Guan, Zhong
影响因子：
8
作者：
通讯作者：
--
DOI：
10.1073/pnas.96.4.1403
发表时间：
1999-02-16
影响因子：
11.1
作者：
Kurimasa, A;Ouyang, H;Li, GC
通讯作者：
Li, GC
DOI：
10.1084/jem.186.6.921
发表时间：
1997-09-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ouyang H;Nussenzweig A;Kurimasa A;Soares VC;Li X;Cordon-Cardo C;Li Wh;Cheong N;Nussenzweig M;Iliakis G;Chen DJ;Li GC
通讯作者：
Li GC
早期 T 期鼻咽癌外照射放疗后 3D 图像引导 HDR 近距离放射治疗与 2D HDR 近距离放射治疗的比较
影响因子：
3.8
作者：
Ren Y;Zhao Q;Liu H;Huang Y;Wang Z;Cao X;Teh BS;Wen B
通讯作者：
Wen B