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

摘要

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.