ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage.
ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage.
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ZEB1 抑制通过消除上皮-间质转化并增强 DNA 损伤，使细胞对 ATR 抑制剂 VE-821 敏感
DOI：
10.1080/15384101.2017.1404206
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发表时间：
2017
期刊：
影响因子：
4.3
通讯作者：
车晓芳
中科院分区：
文献类型：
--
作者：
宋娜;荆薇;李策;白茗;成宇;李贺明;侯科佐;李艳荣;王凯;李智;刘云鹏;曲秀娟;车晓芳
ataxa -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发挥重要作用。在各种肿瘤中，癌细胞对ATR信号的生存依赖性增加，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，但单独应用ATR抑制剂效果有限。在本研究中，我们研究了上皮-间质转化（EMT）和EMT转录因子ZEB1在调节细胞对ATR抑制剂VE-821的敏感性中的作用。我们发现VE-821诱导EMT的同时伴有ZEB1的上调，并促进了VE-821抗增殖作用有限的细胞的迁移。使用siRNA敲除ZEB1部分逆转VE-821诱导的EMT，并通过有效衰减迁移和AKT/ERK信号通路使细胞对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，VE-821联合ZEB1抑制可促进DNA损伤积累。这些结果表明，EMT代表了限制ATR抑制剂有效性的新机制，因此表明ZEB1抑制可能代表了提高ATR抑制剂效率或逆转对ATR抑制剂耐药性的新途径。
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.