Purpose: Dioscin, a natural glycoside derived from many plants, has been proved to exert anti-cancer activity. Several studies have found that it reverses TGF-β1-induced epithelial– mesenchymal transition (EMT). Whether dioscin can reverse EMT by pathways other than TGF-β is still unknown. Methods: We used network-based pharmacological methods to systematically explore the potential mechanisms by which dioscin acts on lung cancer. Cell Counting Kit-8 assay, scratch healing, Transwell assay, Matrigel invasion assay, immunofluorescence assay, and Western blotting were employed to confirm the prediction of key targets and the effects of dioscin on EMT. Results: Here, using network-based pharmacological methods, we found 42 possible lung cancer-related targets of dioscin, which were assigned to 98 KEGG pathways. Among the 20 with the lowest p-values, the PI3K-AKT signaling pathway is involved and significantly related to EMT. AKT1 and mTOR, with high degrees (reflecting higher connectivity) in the compound-target analysis, participate in the PI3K-AKT signaling pathway. Molecular docking indicated the occur-rence of dioscin-AKT1 and dioscin-mTOR binding. Functional experiments demonstrated that dioscin suppressed the proliferation, migration, invasion, and EMT of human lung adenocarcinoma cells in a dose-dependent manner, without TGF-β stimulation. Furthermore, we determined that dioscin downregulated p-AKT, p-mTOR and p-GSK3β in human lung adenocarcinoma cells without affecting their total protein levels. The PI3K inhibitor LY294002 augmented these changes. Conclusion: Dioscin suppressed proliferation, invasion and EMT of lung adenocarcinoma cells via the inactivation of AKT/mTOR/GSK3β signaling, probably by binding to AKT and mTOR, and inhibiting their phosphorylation.
CITATION STYLE
Mao, W., Yin, H., Chen, W., Zhao, T., Wu, S., Jin, H., … He, Y. (2020). Network pharmacology and experimental evidence reveal dioscin suppresses proliferation, invasion, and emt via akt/gsk3b/mtor signaling in lung adenocarcinoma. Drug Design, Development and Therapy, 14, 2135–2147. https://doi.org/10.2147/DDDT.S249651
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