<p>Network Pharmacology and Experimental Evidence Reveal Dioscin Suppresses Proliferation, Invasion, and EMT via AKT/GSK3b/mTOR Signaling in Lung Adenocarcinoma</p>

Abstract

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 epithelialmesenchymal 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 cancerrelated 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 occurrence 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.

Neutrophil extracellular DNA traps promote pancreatic cancer cells migration and invasion by activating EGFR/ERK pathway

“…To determine the mechanical link between NETs and EMT in pancreatic cancer cells, we investigated several important EMT relative pathways such as EGFR, 31 WNT, 32 TGF‐β, 33 AKT 34 and mTOR 35 pathway.…”

Yang-Yin-Jie-Du decoction overcomes gefitinib resistance in non-small cell lung cancer via down-regulation of the PI3K/Akt signalling pathway

“…Dioscin could suppress the viability of various cancer cells (ovarian cancer, lung cancer, gallbladder, etc.) by regulating the PI3K/Akt pathway (Song et al 2017;Guo and Ding 2018;Mao et al 2020). Lobetyolin was proven that its inhibitory effect on breast cancer cells was related to Akt (Chen et al 2021).…”

Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies

“…Some other signaling pathways such as PI3K/Akt/mTOR and p38/MAPK/JNK are also reported for the anticancer activities of dioscin ( Li X. L. et al, 2021 ). Molecular docking suggests that dioscin can bind to AKT and mTOR to inhibit their phosphorylation ( Mao et al, 2020 ).…”