Network Pharmacology and Experimental Evidence Reveal Dioscin Suppresses Proliferation, Invasion, and EMT via AKT/GSK3b/mTOR Signaling in Lung Adenocarcinoma.
Drug Des Devel Ther
; 14: 2135-2147, 2020.
Article
en En
| MEDLINE
| ID: mdl-32546976
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-ß1-induced epithelial-mesenchymal transition (EMT). Whether dioscin can reverse EMT by pathways other than TGF-ß 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-ß stimulation. Furthermore, we determined that dioscin downregulated p-AKT, p-mTOR and p-GSK3ß 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/GSK3ß signaling, probably by binding to AKT and mTOR, and inhibiting their phosphorylation.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diosgenina
/
Proteínas Proto-Oncogénicas c-akt
/
Adenocarcinoma del Pulmón
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Neoplasias Pulmonares
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Drug Des Devel Ther
Asunto de la revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Año:
2020
Tipo del documento:
Article