Diosgenin and GSK126 Produce Synergistic Effects on Epithelial–Mesenchymal Transition in Gastric Cancer Cells by Mediating EZH2 via the Rho/ROCK Signaling Pathway
Autor: | Lijun Geng, Zhi-Neng Zeng, Guihong Rong, Jun Yang, Shanshan Liu, Xia Li, Ye-sheng Wei, Dong-xiang Jiang |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cell 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Pharmacology (medical) EZH2 Viability assay Original Research Rho/ROCK Chemistry Cell growth gastric cancer EMT Diosgenin Cell cycle 030104 developmental biology medicine.anatomical_structure Oncology Apoptosis diosgenin 030220 oncology & carcinogenesis Cancer cell Cancer research G1 phase |
Zdroj: | OncoTargets and therapy |
ISSN: | 1178-6930 |
Popis: | Background Diosgenin, a natural steroidal saponin isolated from Trigonella foenum-graecum, has been reported to exert anti-cancer effects. Inhibitors of enhancer of zeste homology 2 (EZH2) have been widely used in treatment of cancers. However, the effects of combined treatment with diosgenin and an EZH2 inhibitor on gastric cancer (GC) cells, and the mechanism for those effects are not fully understood. Methods AGS and SGC-7901 gastric cancer cells were treated with diosgenin (0 to 8 μM), followed by treatment with either diosgenin or an EZH2 inhibitor, GSK126 alone. Afterwards, an EZH2 overexpression plasmid and Rho inhibitor, GSK429286A was involved in cells. Cell proliferation, cell cycle distribution, and cell apoptosis, migration, and invasion were examined by CCK-8 assays, flow cytometry, and transwell assays. Western blotting was performed to detect the relative levels of protein expression. Results Treatment with diosgenin alone caused a dose-dependent decrease in the cell viability, and combined treatment with an EZH2 inhibitor plus GSK126 caused a further significant decrease. A further analysis revealed that treatment with either diosgenin or GSK126 alone induced significant increases in G0/G1 cell cycle arrest and apoptosis, and combined treatment with both agents induced further increases in those parameters. In addition, combined treatment with diosgenin and GSK126 synergistically induced even stronger effects on impaired cell proliferation, G0/G1 phase arrest, and cell apoptosis when compared to treatment with either diosgenin or GSK126 treatment alone. At the molecular level, we demonstrated that inhibition of Rho/ROCK signaling by combined treatment with diosgenin and GSK126 could downregulate the expression of epithelial-mesenchymal transition (EMT)-related molecules. We also found that EZH2 overexpression reversed the anti-tumor effect of diosgenin by inducing cell survival, blocking G1-phase arrest, and promoted EMT. While, these biological properties were further reversed by GSK429286A. Conclusion Collectively, combined treatment with diosgenin and GSK126 produced even more significant effects on GC cell inhibition by targeting EZH2 via Rho/ROCK signaling-mediated EMT, which might be a therapeutic strategy for improving the poor therapeutic outcomes obtained with GSK126 monotherapy. |
Databáze: | OpenAIRE |
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