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Cited by 215Cancer Cells and MetastasisLung Cancer Treatments and MutationsMechanisms of cancer metastasis

Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway

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Shen, Mingjing, Xu, Zhonghua, Xu, Weihua, Jiang, Kanqiu, Zhang, Fuquan, Ding, Qifeng, Xu, Zhonghen, Chen, Yongbing·2019·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-019-1161-8PMC PMC6454747
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Abstract

The cisplatin-resistance is still a main course for chemotherapy failure of lung cancer patients. Cisplatin-resistant cancer cells own higher malignance and exhibited increased metastatic ability, but the mechanism is not clear. In this study, we investigated the effects of Ataxia Telangiectasia Mutated (ATM) on lung cancer metastasis. Cisplatin-resistant A549CisR and H157CisR cell line were generated by long-term treating parental A549 and H157 cells (A549P and H157P) with cisplatin. Cell growth, cell migration and cell invasion were determined. Gene expressions were determined by Western Blot and qPCR. Tumor metastasis was investigated using a xenograft mouse model. The IC50 of the cisplatin-resistant cells (A549CisR and H157CisR cells) to cisplatin was 6–8 higher than parental cells. The A549CisR and H157CisR cells expressed lower level of E-cadherin and higher levels of N-cadherin, Vimentin and Snail compared to the parental A549P and H157P cells, and exhibited stronger capabilities of metastatic potential compared to the parental cells. The ATM expression was upregulated in A549CisR and H157CisR cells and cisplatin treatment also upregulated expression of ATM in parental cells, The inhibition of ATM by using specific ATM inhibitor CP466722 or knock-down ATM by siRNA suppressed Epithelial-to-Mesenchymal transition (EMT) and metastatic potential of A549CisR and H157CisR cells. These data suggest that ATM mediates the cisplatin-resistance in lung cancer cells. Expressions of JAK 1,2, 、 STAT 3 、PD-L1 and ATM were increased in A549CisR and H157CisR cells and could by induced by cisplatin in parental lung cancer cells. Interestedly, ATM upregulated PD-L1 expression via JAK 1,2 /STAT 3 pathway and inhibition of ATM decreased JAK/STAT3 signaling and decreased PD-L1 expression. The treatment of PD-L1 neutralizing Ab reduced EMT and cell invasion. Inhibition of JAK 1,2 /STAT 3 signaling by specific inhibitors suppressed ATM-induced PD-L1 expression, EMT and cell invasion. Importantly, inhibition of ATM suppressed EMT and tumor metastasis in cisplatin-resistant lung cancer cells in an orthotopic xenograft mouse model. Our results show that ATM regulates PD-L1 expression through activation of JAK/STAT3 signaling in cisplatin-resistant cells. Overexpression of ATM contributes to cisplatin-resistance in lung cancer cells. Inhibition of ATM reversed EMT and inhibited cell invasion and tumor metastasis. Thus, ATM may be a potential target for the treatment of cisplatin-resistant lung cancer.

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  • STAT3 partially coordinates the cisplatin-resistance phenotype in non-small-cell lung cancer.

    “In addition, STAT3 partially coordinates the cisplatin-resistance phenotype in non–small-cell lung cancer, providing support for the combination of cisplatin, rapamycin, and STAT3 abrogation as a rational therapeutic approach for lung cancer (57).”

    From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [57]

    The Results section ('ATM up-regulate PD-L1 through JAK1,2/STAT3 pathway') reports increased STAT3 signaling in cisplatin-resistant NSCLC cells and reduced invasion when STAT3 was inhibited. This supports a role for STAT3 in features of those cells, but the paper does not show that STAT3 inhibition reverses cisplatin resistance or test the proposed cisplatin–rapamycin–STAT3 combination. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The combination of cisplatin, rapamycin, and STAT3 abrogation is a rational therapeutic approach for lung cancer.

    “providing support for the combination of cisplatin, rapamycin, and STAT3 abrogation as a rational therapeutic approach for lung cancer (57).”

    From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [57]

    The Background (page unavailable) describes cisplatin as a lung-cancer treatment, and the Results (page unavailable) link STAT3 signaling to cisplatin-resistant lung-cancer cells. But the Conclusions (page unavailable) propose targeting ATM, not a combination of cisplatin, rapamycin, and STAT3 abrogation; a search for rapamycin found no relevant passage in our copy. (LLM, conf=0.88)

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References 42 · Cited by 215

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Authors
Shen, M., Xu, Z., Xu, W., Jiang, K., Zhang, F., Ding, Q., Xu, Z., & Chen, Y.
Affiliations
Second Affiliated Hospital of Soochow University (CN)
Corresponding author
  • Xu, Zhonghen
  • Chen, Yongbing
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2019-04-08
Volume
38
Issue
1
Pages
149-149
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-019-1161-8
PMC
PMC6454747
OpenAlex
W2946710419
Cited by
215
References
42
Citations by year
2026: 21 · 2025: 37 · 2024: 36 · 2023: 35 · 2022: 30 · 2021: 33 · 2020: 17 · 2019: 6
FWCI
8.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Suzhou science and technology foundation (SYS2018064)
  • Hospital internal research foundation for PhD (Hospital internal research foundation for PhD)
  • Jiangsu Provincial Commission of Health and Family Planning (H201521)
  • Natural Science Foundation of Jiangsu Province (Natural Science Foundation of Jiangsu Province)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
ATM, cisplatin resistance, lung cancer, epithelial-mesenchymal transition, metastasis, JAK/STAT3 signaling, PD-L1, E-cadherin, N-cadherin, snails, cell invasion, cell migration, A549 cells, H157 cells
MeSH terms
Animals, Ataxia Telangiectasia, Humans, Lung Neoplasms, Neoplasm Metastasis, STAT3 Transcription Factor, Mice, Epithelial-Mesenchymal Transition, Ataxia Telangiectasia Mutated Proteins

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