Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer
| العنوان: | Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer |
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| المؤلفون: | Jianyun Zhu, Xu Zhou, Yue Chen, Caiyun Zhong, Chunhua Liang, Juan Yin, Miaomiao Ge, Xiaoting Li, Chunfeng Xie |
| المصدر: | Journal of Experimental & Clinical Cancer Research : CR Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-18 (2021) |
| بيانات النشر: | BioMed Central, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, STAT3 Transcription Factor, Cancer Research, Cell cycle checkpoint, Epithelial-Mesenchymal Transition, Lung Neoplasms, NF-E2-Related Factor 2, Pyridines, Caspase 3, Apoptosis, NSCLC, Jurkat cells, B7-H1 Antigen, Flow cytometry, chemistry.chemical_compound, Mice, Cell Movement, Cell Line, Tumor, STAT3/PD-L1, medicine, Autophagy, Animals, Humans, Apatinib, neoplasms, RC254-282, Cell Proliferation, medicine.diagnostic_test, Chemistry, Cell growth, Research, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Correction, Cell Cycle Checkpoints, Cell cycle, Vascular Endothelial Growth Factor Receptor-2, Xenograft Model Antitumor Assays, respiratory tract diseases, Disease Models, Animal, Oncology, Cancer research, Neoplastic Stem Cells, ROS/Nrf2/p62, Reactive Oxygen Species, Signal Transduction |
| الوصف: | Background Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. Methods MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. Results We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Conclusion Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02069-4. Highlights Apatinib suppressed proliferation, induced cell cycle arrest and apoptosis, and inhibited malignancy in NSCLC in vitro and in vivo.Apatinib downregulated PD-L1 and c-Myc in NSCLC through VEGFR2/STAT3 pathway.Apatinib inhibited PD-L1 expression in THP-1 derived macrophages stimulated by the conditioned medium from NSCLC cells and partially restored the activation of Jurkat T cells co-cultured with NSCLC cells.Apatinib induced ROS generation and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02069-4. |
| اللغة: | English |
| تدمد: | 1756-9966 0392-9078 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::212a9efdd1b5ff9e270bfdd04b4787cf http://europepmc.org/articles/PMC8385858 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....212a9efdd1b5ff9e270bfdd04b4787cf |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 17569966 03929078 |
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