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

Abstract

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 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.

• Authors: Wenli Mao, Heng Yin, Wenya Chen, Tingxiu Zhao, Shaofeng Wu, He Jin, Biaoyan Du, Yuhui Tan, Ren Zhang, Yanli He
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 14 Pg. 2135-2147 ( 2020) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 32546976 (Publication Type: Journal Article)
• Copyright: © 2020 Mao et al.

Chemical References

• Antineoplastic Agents
• dioscin
• MTOR protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Diosgenin

Topics

• A549 Cells
• Adenocarcinoma of Lung (drug therapy, metabolism, pathology)
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Diosgenin (analogs & derivatives, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Epithelial-Mesenchymal Transition (drug effects)
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, metabolism)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)