1. Cancer Biology

Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase

  1. Ning Yang
  2. Xuebo Lu
  3. Yanan Jiang
  4. Lili Zhao
  5. Donghao Wang
  6. Yaxing Wei
  7. Yin Yu
  8. Myoung Ok Kim
  9. Kyle Vaughn Laster
  10. Xin Li
  11. Baoyin Yuan
  12. Zigang Dong  Is a corresponding author
  13. Kangdong Liu  Is a corresponding author
  1. Zhengzhou University, China
  2. Kyungpook National University, Republic of Korea
  3. China-US Hormel Cancer Institute, China
https://doi.org/10.7554/eLife.73953
Share this article
Cite this article
  1. Ning Yang
  2. Xuebo Lu
  3. Yanan Jiang
  4. Lili Zhao
  5. Donghao Wang
  6. Yaxing Wei
  7. Yin Yu
  8. Myoung Ok Kim
  9. Kyle Vaughn Laster
  10. Xin Li
  11. Baoyin Yuan
  12. Zigang Dong
  13. Kangdong Liu
(2022)
Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase
eLife 11:e73953.
https://doi.org/10.7554/eLife.73953
  2. Download BibTeX
  3. Download .RIS

Abstract

Human esophageal cancer has a global impact on human health due to its high incidence and mortality. Therefore, there is an urgent need to develop new drugs to treat or prevent the prominent pathological subtype of esophageal cancer, esophageal squamous cell carcinoma. Based upon a screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of human esophageal squamous cell carcinoma in vitro. Next, we conducted a series of cell-based assays and found that Arbidol treatment inhibited the proliferation and colony formation ability of ESCC cells and promoted G1 phase cell cycle arrest. Phospho-proteomics experiments, in vitro kinase assays and pull-down assays were subsequently performed in order to identify the underlying growth inhibitory mechanism. We verified Arbidol is a potential ATR inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of MCM2 at Ser108. Finally, we demonstrated Arbidol had the inhibitory effect of ESCC in vivo by a PDX model. All together, Arbidol inhibits the proliferation of ESCC in vitro and in vivo through the DNA replication pathway and is associated with the cell cycle.

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD034944.

The following data sets were generated

Article and author information

Author details

  1. Ning Yang

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Xuebo Lu

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Yanan Jiang

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Lili Zhao

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Donghao Wang

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Yaxing Wei

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Yin Yu

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Myoung Ok Kim

    Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.

  9. Kyle Vaughn Laster

    China-US Hormel Cancer Institute, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Xin Li

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  11. Baoyin Yuan

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  12. Zigang Dong

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    For correspondence
    dongzg@zzu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  13. Kangdong Liu

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    For correspondence
    kdliu@zzu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4425-5625

Funding

National Natural Science Foundation of China (81872335)

  • Kangdong Liu

National Natural Science Youth Foundatio of China (81902486)

  • Yanan Jiang

Natural Science Foundation of Henan (161100510300)

  • Kangdong Liu

The Central Plains Science and Technology Innovation Leading Talents (224200510015)

  • Kangdong Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Compliance with Ethics RequirementsIn this study, we established an ESCC PDX model. In this model, the tumor sample from an ESCC patient was EG20 (ESCC, male, T2N0M0II, moderately differentiated, obtained from Linzhou Cancer Hospital, Henan Province, China). The patient was fully informed of the study and provided consent. This study was approved by the Ethics Committee of Zhengzhou University (ZZUHCI-2019012).

Copyright

© 2022, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 607
    views
  • 165
    downloads
  • 1
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ning Yang
  2. Xuebo Lu
  3. Yanan Jiang
  4. Lili Zhao
  5. Donghao Wang
  6. Yaxing Wei
  7. Yin Yu
  8. Myoung Ok Kim
  9. Kyle Vaughn Laster
  10. Xin Li
  11. Baoyin Yuan
  12. Zigang Dong
  13. Kangdong Liu
(2022)
Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase
eLife 11:e73953.
https://doi.org/10.7554/eLife.73953

Share this article

https://doi.org/10.7554/eLife.73953

Categories and tags

Further reading

    1. Cancer Biology
    2. Genetics and Genomics

    Combinatorial CRISPR screen reveals FYN and KDM4 as targets for synergistic drug combination for treating triple negative breast cancer

    Tackhoon Kim, Byung-Sun Park ... Timothy Lu
    Research Article

    Tyrosine kinases play a crucial role in cell proliferation and survival and are extensively investigated as targets for cancer treatment. However, the efficacy of most tyrosine kinase inhibitors (TKIs) in cancer therapy is limited due to resistance. In this study, we identify a synergistic combination therapy involving TKIs for the treatment of triple negative breast cancer. By employing pairwise tyrosine kinase knockout CRISPR screens, we identify FYN and KDM4 as critical targets whose inhibition enhances the effectiveness of TKIs, such as NVP-ADW742 (IGF-1R inhibitor), gefitinib (EGFR inhibitor), and imatinib (ABL inhibitor) both in vitro and in vivo. Mechanistically, treatment with TKIs upregulates the transcription of KDM4, which in turn demethylates H3K9me3 at FYN enhancer for FYN transcription. This compensatory activation of FYN and KDM4 contributes to the resistance against TKIs. FYN expression is associated with therapy resistance and persistence by demonstrating its upregulation in various experimental models of drug-tolerant persisters and residual disease following targeted therapy, chemotherapy, and radiotherapy. Collectively, our study provides novel targets and mechanistic insights that can guide the development of effective combinatorial targeted therapies, thus maximizing the therapeutic benefits of TKIs.

    1. Cancer Biology
    2. Genetics and Genomics

    Functional characterization of all CDKN2A missense variants and comparison to in silico models of pathogenicity

    Hirokazu Kimura, Kamel Lahouel ... Nicholas Jason Roberts
    Research Article

    Interpretation of variants identified during genetic testing is a significant clinical challenge. In this study, we developed a high-throughput CDKN2A functional assay and characterized all possible human CDKN2A missense variants. We found that 17.7% of all missense variants were functionally deleterious. We also used our functional classifications to assess the performance of in silico models that predict the effect of variants, including recently reported models based on machine learning. Notably, we found that all in silico models performed similarly when compared to our functional classifications with accuracies of 39.5–85.4%. Furthermore, while we found that functionally deleterious variants were enriched within ankyrin repeats, we did not identify any residues where all missense variants were functionally deleterious. Our functional classifications are a resource to aid the interpretation of CDKN2A variants and have important implications for the application of variant interpretation guidelines, particularly the use of in silico models for clinical variant interpretation.

    1. Cancer Biology
    2. Developmental Biology

    Oncogenic and teratogenic effects of Trp53Y217C, an inflammation-prone mouse model of the human hotspot mutant TP53Y220C

    Sara Jaber, Eliana Eldawra ... Franck Toledo
    Research Article

    Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in Trp53Y217C/Y217C (Trp53YC/YC) cells, and Trp53YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53-/- cells. Furthermore, Trp53YC/YC male mice died earlier than Trp53-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53YC/YC thymic cells compared to Trp53-/- cells. Surprisingly, we recovered only one Trp53YC/YC female for 22 Trp53YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53YC/YC female embryos with exencephaly and the death of most Trp53YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53YC/YC weaned females in their progeny. Together, these data suggest that the p53Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.