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Diosgenin Suppresses Cholangiocarcinoma Cells Via Inducing Cell Cycle Arrest And Mitochondria-Mediated Apoptosis
Xiao-Mei Mao1, Pan Zhou1, Si-Yang Li2
1School of Life Sciences, Xiamen University, Xiamen 361102, People's Republic of China.
Purpose:
Diosgenin (DSG) is the precursor of steroid hormones and plays a crucial part in the proliferation of various carcinomas including human colorectal cancer and gastric carcinoma. Nevertheless, its specific features and mechanisms in human cholangiocarcinoma (CCA) remain unknown.
Methods:
MTS assay, colony-forming assay, and EdU assay were performed to determine the role of DSG on the progression of human CCA cells. The distributions of cell cycle, the ratio of apoptosis, and the mitochondrial membrane potential (ΔΨm) were studied by flow cytometry (FCM). AO/EB and Hoechst 33258 staining were performed to observe the morphological features of cell apoptosis. TEM was performed to observe the ultrastructures of QBC939 and HuCCT1 cells. The mRNA and protein expression of mitochondrial apoptotic pathway and GSK3β/β-catenin pathway were further confirmed by qPCR and Western blotting. The xenograft tumor model of HuCCT1 cells was built. Immunohistochemistry of tumor tissues was performed.
Results:
Our results indicated that DSG inhibited the progression of six CCA cell lines. In vivo tumor studies also indicated that DSG significantly inhibited tumor growth in xenografts in nude mice. The expression of mitosis-promoting factor cyclinB1 was decreased along with the elevating level of cell cycle inhibitor p21, resulting in arresting CCA cell cycles at G2/M phase. Furthermore, DSG induced apoptosis with the increased expressions of cytosol cytochrome C, cleaved-caspase-3, cleaved-PARP1 and the Bax/Bcl-2 ratio. Mechanistically, our study showed that GSK3β/β-catenin pathway was involved in the apoptosis of CCA cells. Thus, DSG might provide a new clue for the drug therapy of CCA.
Conclusion:
In our data, DSG was found to have efficient antitumor potential of human CCA cells in vitro and in vivo.
Insights
Diosgenin (DSG) effectively inhibits human cholangiocarcinoma (CCA) progression by arresting cell cycles and inducing apoptosis. This natural compound shows significant antitumor potential in both cell lines and animal models, offering a promising therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Diosgenin (DSG) is a steroid hormone precursor implicated in various cancer progressions.
- The specific role and mechanisms of DSG in human cholangiocarcinoma (CCA) remain largely uncharacterized.
Purpose of the Study:
- To investigate the antitumor effects of Diosgenin (DSG) on human cholangiocarcinoma (CCA) cells.
- To elucidate the underlying molecular mechanisms of DSG-induced cell cycle arrest and apoptosis in CCA.
Main Methods:
- Cell viability, proliferation, and apoptosis assays (MTS, colony formation, EdU, AO/EB, Hoechst staining).
- Cell cycle distribution and mitochondrial membrane potential analysis via flow cytometry.
- Ultrastructural observation using Transmission Electron Microscopy (TEM).
- Gene and protein expression analysis (qPCR, Western blotting) of key apoptotic and signaling pathways.
- In vivo efficacy assessment using a xenograft tumor model in nude mice.
Main Results:
- DSG significantly inhibited the proliferation of multiple human CCA cell lines in vitro.
- DSG treatment led to cell cycle arrest at the G2/M phase, evidenced by decreased cyclinB1 and increased p21 expression.
- DSG induced apoptosis through the mitochondrial pathway, indicated by increased Bax/Bcl-2 ratio, cytochrome C release, and caspase-3/PARP1 cleavage.
- DSG demonstrated significant tumor growth inhibition in a xenograft mouse model.
- The GSK3β/β-catenin pathway was identified as a key mediator of DSG's pro-apoptotic effects in CCA.
Conclusions:
- Diosgenin (DSG) exhibits potent antitumor activity against human cholangiocarcinoma (CCA) in vitro and in vivo.
- DSG-induced apoptosis and cell cycle arrest present a promising therapeutic strategy for CCA.
- Further research into DSG as a potential chemotherapeutic agent for CCA is warranted.
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