ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage

Song Na; Jing Wei; Li Ce; Bai Ming; Cheng Yu; Li Heming; Hou Kezuo; Li Yanrong; Wang Kai; Li Zhi; Liu Yunpeng; Qu Xiujuan; Che Xiaofang

首页> 外文期刊>Cell cycle >ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage

【24h】

ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage

机译：Zeb1抑制通过消除上皮 - 间充质转变和增强DNA损伤，使细胞对ATR抑制剂Ve-821感染

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相似文献
相关主题

摘要

The ataxia-telangiectasia-mutated (ATM) and rad3-related (ATR) checkpoint pathway plays an essential role in modulating cellular responses to replication stress and DNA damage to maintain genomic stability. In various tumors, cancer cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. ATR inhibitors sensitize multiple tumor cell types to radiation and DNA-damaging agents, but application of an ATR inhibitor alone shows limited efficacy. In the present study, we investigated the role of epithelial-to-mesenchymal transition (EMT) and the EMT transcription factor ZEB1 in regulating cell sensitivity to the ATR inhibitor VE-821. We found that VE-821 induced EMT with concomitant ZEB1 upregulation and promoted migration in cells in which the anti-proliferative effect of VE-821 was limited. Knocking down ZEB1 using siRNA partially reversed VE-821-induced EMT, and sensitized cells to VE-821 via effective attenuation of migration and AKT/ERK signaling. Moreover, ZEB1 inhibition promoted Chk1 phosphorylation and induced S-phase arrest by enhancing TopBP1 expression, which suggests a distinctive modulatory effect of ZEB1 on Chk1. Finally, combining VE-821 with ZEB1 inhibition enhanced DNA damage accumulation. These results demonstrate that EMT represents a novel mechanism for limiting the effectiveness of an ATR inhibitor, and thus suggest that ZEB1 inhibition might represent a new approach to increasing the efficiency of, or reversing resistance to, ATR inhibitors.

机译：共济失调毛细血管扩张突变（ATM）和rad3相关（ATR）检查点通路在调节细胞对复制应激和DNA损伤的反应以维持基因组稳定性方面起着重要作用。在各种肿瘤中，癌细胞对ATR信号的依赖性增加，使ATR成为癌症治疗的一个有希望的靶点。ATR抑制剂使多种肿瘤细胞对辐射和DNA损伤剂敏感，但仅应用ATR抑制剂的效果有限。在本研究中，我们研究了上皮-间充质转化（EMT）和EMT转录因子ZEB1在调节细胞对ATR抑制剂VE-821敏感性中的作用。我们发现，在VE-821的抗增殖作用有限的细胞中，VE-821诱导EMT并伴随ZEB1上调，并促进迁移。使用siRNA敲除ZEB1部分逆转了VE-821诱导的EMT，并通过有效抑制迁移和AKT/ERK信号使细胞对VE-821敏感。此外，ZEB1抑制通过增强TopBP1表达促进Chk1磷酸化并诱导S期阻滞，这表明ZEB1对Chk1具有独特的调节作用。最后，结合VE-821和ZEB1抑制增强了DNA损伤累积。这些结果表明，EMT代表了一种限制ATR抑制剂有效性的新机制，因此表明ZEB1抑制可能代表了一种提高ATR抑制剂效率或逆转其耐药性的新方法。

著录项

来源
《Cell cycle》 |2018年第5期|共10页
作者
Song Na; Jing Wei; Li Ce; Bai Ming; Cheng Yu; Li Heming; Hou Kezuo; Li Yanrong; Wang Kai; Li Zhi; Liu Yunpeng; Qu Xiujuan; Che Xiaofang;
展开▼
作者单位

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Oncol Shengjing Hosp Shenyang 110004 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

Dalian Univ Dept Oncol Affiliated Zhongshan Hosp Dalian 116001 Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

China Med Univ Dept Med Oncol Hosp 1 Shenyang 110001 Liaoning Peoples R China;

展开▼
收录信息
原文格式 PDF
正文语种 eng
中图分类细胞生物学;
关键词
ATR; Chk1; EMT; ZEB1; ATR inhibitor; sensitivity; DNA damage;

机译：ATR;CHK1;EMT;Zeb1;ATR抑制剂;敏感性;DNA损伤;

相似文献

外文文献
中文文献
专利

1. Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair [J] . Xiao-qin LI, Jin REN, Ping CHEN, 中国药理学报：英文版 . 2018,第008期
2. Tumor suppressor miR-128-3p inhibits metastasis and epithelial-mesenchymal transition by targeting ZEB1 in esophageal squamous-cell cancer [J] . Lili Zhao, Rui Li, Shanling Xu, 生物化学与生物物理学报：英文版 . 2018,第002期
3. Inhibition of Nonsmall Cell Lung Cancer Cell Migration by Protein Arginine Methyltransferase 1-small Hairpin RNA Through Inhibiting Epithelial-mesenchymal Transition,Extracellular Matrix Degradation, and Src Phosphorylation In Vitro [J] . Ting Zhang, Ge Cui, Yun-Liang Yao, 中华医学杂志（英文版） . 2015,第009期
4. mTORC1 inhibitor RAD001 (everolimus) enhances non-small cell lung cancer cell radiosensitivity in vitro via suppressing epithelial-mesenchymal transition [J] . Yu Chen, Wen-wen LI, Ping Peng, 中国药理学报：英文版 . 2019,第008期
5. ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage [J] . Song Na, Jing Wei, Li Ce, Cell cycle . 2018,第5期

机译：Zeb1抑制通过消除上皮 - 间充质转变并增强DNA损伤，使细胞敏化细胞到ATR抑制剂VE-821
6. ATR Inhibitors VE-821 and VX-970 Sensitize Cancer Cells to Topoisomerase I Inhibitors by Disabling DNA Replication Initiation and Fork Elongation Responses [J] . Josse Rozenn, Martin Scott E., Guha Rajarshi, Cancer research: The official organ of the American Association for Cancer Research, Inc . 2014,第23期

机译：ATR抑制剂VE-821和VX-970通过禁用DNA复制起始和前叉延伸反应使癌细胞对拓扑异构酶I抑制剂敏感。
7. Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to Chemotherapy by Abrogating the TopBP1/ATR-Mediated DNA Damage Response [J] . Li Ding, Vijay S. Madamsetty, Spencer Kiers, Clinical cancer research: an official journal of the American Association for Cancer Research . 2019,第21期

机译：糖原合成酶激酶-3抑制通过废除TOPBP1 / ATR介导的DNA损伤反应来使胰腺癌细胞敏化胰腺癌细胞。
8. 8-oxoG DNA glycosylase-1 inhibition sensitizes Neuro-2a cells to oxidative DNA base damage induced by 900 MHz radiofrequency electromagnetic radiation [C] . Zhou Zhou, Lei Zhang, Chuan Liu, Joint Meeting of the Bioelectromagnetics Society and the European BioElectromagnetics Association . 2018

机译：8-Oxog DNA糖基酶-1抑制抑制Neuro-2a细胞对900MHz射频电磁辐射引起的氧化DNA碱基损伤
9. Extracellular vesicle-encapsulated miR-30e suppresses　cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition [D] . 太田, 雄 2019

机译：细胞外囊泡包裹的miR-30e通过抑制上皮-间质转化抑制胆管癌细胞的侵袭和迁移
10. ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial–mesenchymal transition and enhancing DNA damage [O] . Na Song, Wei Jing, Ce Li, 2018

机译：ZEB1抑制通过消除上皮-间质转化并增强DNA损伤而使细胞对ATR抑制剂VE-821敏感
11. Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair [O] . Xiao-qin Li, Jin Ren, Ping Chen, 2018

机译：POLη和ATR的共同抑制通过阻碍DNA损伤修复使顺铂抗性非小细胞肺癌细胞敏化为顺铂
12. Inhibition of the Pin1 Prolyl Isomerase: A Novel Approach for DNA checkpoint Abrogation in Breast Cancer Cell Lines. [R] . Vandre, D. D. 2001

机译：抑制pin1脯氨酰异构酶：一种新的乳腺癌细胞系DNa检查点消除方法。

ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage

摘要

著录项

相似文献

相关主题

期刊订阅