ArticleCell cycle (Georgetown, Tex.)2018
ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage.
Article in Cell cycle (Georgetown, Tex.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Local growth hormone promotes benign prostatic hyperplasia.JCI insight · 2026Article
- DNA damage-induced EMT controlled by the PARP-dependent chromatin remodeler ALC1 promotes DNA repair efficiency through RAD51 in tumor cells.Molecular biology of the cell · 2024Article
- Role of EMT in the DNA damage response, double-strand break repair pathway choice and its implications in cancer treatment.Cancer science · 2022Review
- Regulatory pathways and drugs associated with ferroptosis in tumors.Cell death & disease · 2022Review
- Dynamic EMT: a multi-tool for tumor progression.The EMBO journal · 2021Review
- G2/M Checkpoint Abrogation With Selective Inhibitors Results in Increased Chromatid Breaks and Radiosensitization of 82-6 hTERT and RPE Human Cells.Frontiers in public health · 2021Article
- Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer.Redox biology · 2020Article
- PD-L1 upregulation accompanied with epithelial-mesenchymal transition attenuates sensitivity to ATR inhibition in p53 mutant pancreatic cancer cells.Medical oncology (Northwood, London, England) · 2020Article
- ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance.Frontiers in molecular biosciences · 2020Review
- ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation.Cell death & disease · 2019Article
- Epithelial-Mesenchymal Transition: Role in Cancer Progression and the Perspectives of Antitumor Treatment.Acta naturaeArticle
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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