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Nintedanib Induces the Autophagy-Dependent Death of Gastric Cancer Cells by Inhibiting the STAT3/Beclin1 Pathway

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Abstract

Background

Tyrosine kinase inhibitors are currently the most widely studied targeted therapies for gastric cancer. As a triple tyrosine inhibitor, nintedanib can alleviate the progression of a variety of cancers, but it is poorly studied in gastric cancer.

Aims

To investigate the effect of nintedanib on gastric cancer.

Methods

This study investigated nintedanib’s effect on gastric cancer autophagy in vivo and in vitro, and the activity and morphological changes of gastric cancer cells were detected by MTT and HE staining. Proliferation, migration, invasion, and EMT-related marker proteins of AGS and MKN-28 cells were detected. The effects of nintedanib on autophagy in gastric cancer cells were detected by acridine orange, immunofluorescence, and Western blotting assays. The regulation of nintedanib on STAT3 and Beclin1 was detected by qPCR and Western blotting assays. Subsequently, the effects of nintedanib on the tumor STAT3/Beclin1 pathway were verified by stably overexpressing STAT3 in gastric cancer cell lines and tumor-bearing experiments in nude mice.

Results

The results showed that nintedanib could inhibit gastric cancer cells’ proliferation and EMT process. Meanwhile, autophagy was induced in AGS and MKN-28 cells, and the expression of autophagy-related protein Beclin1 was upregulated, and the phosphorylation level of STAT3 was downregulated. Nintedanib inhibited STAT3 phosphorylation and upregulated Beclin1 to inhibit tumor growth in gastric cancer cell lines with stable STAT3 overexpression and tumor-bearing experiments in nude mice.

Conclusions

By inhibiting STAT3, nintedanib upregulated Beclin1 and caused autophagic death in gastric cancer cells.

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Data availability

The datasets used in the current study are available from the corresponding author upon reasonable request.

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Authors and Affiliations

Authors

Contributions

HZ and MMX designed the study and developed the methodology. HZ, MMX, and KHT performed the experiments and collected the data, analyzed and interpreted the data, and wrote the original draft. WBL interpreted the data and critically reviewed the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Hui Zhu.

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There is no conflict of interest for any of the authors.

Ethical approval

Ethic Approval is approved by Ningbo University Animal Testing Center (Grant Number NBU20220118).

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Zhu, H., Xia, MM., Tong, KH. et al. Nintedanib Induces the Autophagy-Dependent Death of Gastric Cancer Cells by Inhibiting the STAT3/Beclin1 Pathway. Dig Dis Sci 68, 1280–1291 (2023). https://doi.org/10.1007/s10620-022-07653-y

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  • DOI: https://doi.org/10.1007/s10620-022-07653-y

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