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Cancer Cell International
Published in: Cancer Cell International 1/2024

Open Access 01-12-2024 | Research

Domperidone inhibits cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma

Authors: Qiang Yuan, Yunshu Shi, Yuhan Zhang, Yaqian Shi, Zubair Hussain, Jimin Zhao, Yanan jiang, Yan Qiao, Yaping Guo, Jing Lu, Ziming Dong, Zigang Dong, Junyong Wang, Kangdong Liu

Published in: Cancer Cell International | Issue 1/2024

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Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of digestive system tumor related death in the world. Unfortunately, effective chemopreventive agent is lack for patients with ESCC in clinical practice, which leads to the extremely high mortality rate.

Methods

A library of prescribed drugs was screened for finding critical anti-tumor properties in ESCC cells. The phosphoproteomics, kinase array, pulldown assay and drug affinity responsive target stabilization assay (DARTS) were applied to explore mechanisms and searched for synergistic targets. Established models of PDX in mice were used to determine the therapeutic effect of domperidone.

Results

After screening a library of prescribed drugs, we discovered that domperidone has anti-tumor properties. Domperidone, acting as a gastroprokinetic agent, has been widely used in clinic for gastrointestinal motility disorders. Despite limited research, there are indications that domperidone may have anti-tumor properties. In this study, we determined that domperidone significantly inhibited ESCC proliferation in vitro and in vivo. We employed phosphoproteomics to reveal p-ERK, and p-SMAD3 down-regulation upon domperidone treatment. Then, the results of kinase assay and pulldown assay further validated that domperidone directly combined with MEK1/2 and CDK4, leading to the inhibition of their kinase activity. Furthermore, our results revealed that MEK/ERK and CDK4/SMAD3 signal pathway were major pathways in domperidone against ESCC.

Conclusion

Collectively, these findings suggest that domperidone serves as an effective “multi-target” inhibitor of MEK1/2 and CDK4, offering potential benefits for the chemoprevention of ESCC.
Appendix
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Metadata
Title
Domperidone inhibits cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma
Authors
Qiang Yuan
Yunshu Shi
Yuhan Zhang
Yaqian Shi
Zubair Hussain
Jimin Zhao
Yanan jiang
Yan Qiao
Yaping Guo
Jing Lu
Ziming Dong
Zigang Dong
Junyong Wang
Kangdong Liu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2024
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-024-03291-8

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