Abstract
Background
Cholangiocarcinoma (CCA) is a malignant epithelial tumor characterized by a dismal prognosis. Given the lack of therapeutic strategies and durable treatment options currently available, identifying innovative treatments for CCA is an urgent unmet clinical need. Cucurbitacin C (CuC) is a distinct variant of the cucurbitacin family, displaying promising anti-cancer activity against various tumor types. The primary objective of our research is to elucidate the promising effects of CuC on CCA.
Methods
The impact of CuC on CCA cell lines was assessed by cell count kit-8 assay, EdU staining assay, colony formation assay, wound-healing assay, and Transwell assay. Flow cytometric analysis was conducted to explore the function of CuC treatments on cell-cycle distribution and apoptosis in CCA cells. Computational biology and network pharmacology approaches were utilized to predict potential targets of CuC. Furthermore, a tumor xenograft mouse model was established using CCA cells to explore the anti-cancer effects of CuC in vivo.
Results
Our research findings revealed that CuC exerted a suppressive effect on CCA cell progression. Cell viability assays, EdU staining assays, and colony formation assays demonstrated that CuC effectively suppressed viability and proliferation of CCA cells. Wound-healing assays and Transwell assays indicated that CuC effectively inhibits the migratory and invasive capabilities of CCA cells. Flow cytometry analysis elucidated that CuC played its anti-proliferative role in CCA cells by arresting G0/G1 phase and increasing apoptosis. Through bioinformatics and network pharmacology analysis, in conjunction with western blot analysis, we demonstrated CuC mediated the inhibition of CCA cell progression through modulation of JAK2/STAT3 pathway. Additionally, the CCA xenograft tumor model was established, and the results supported the inhibition of CuC treatment against CCA progression in vivo.
Conclusion
Our study demonstrates that CuC possesses notable capabilities to suppress cell proliferation, migration, and invasion in CCA. Importantly, the inhibitory effects of CuC on CCA progression are attributed to its modulation of the JAK2/STAT3 signaling pathway. Altogether, our study demonstrated that CuC holds promise as a prospective therapeutic agent for treating CCA.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Acknowledgements
Fig. 6A were adapted and created by Figdraw (www.figdraw.com).
Funding
This study was supported by grants from the Zhejiang Health Committee (2021ZH003), Hangzhou Science and Technology Commission (202004A14), and the Construction Fund of Medical Key Disciplines of Hangzhou (OO20190001).
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WC and JY conceived and designed the experiments. WC performed laboratory experiments, wrote the manuscript, and prepared the figures. ZH and CL conducted data collection and analysis. QL, YW, and JY edited and revised the manuscript. YW and JY provided direction and guidance throughout the writing of this manuscript and shared senior authorship. All authors read and approved the final manuscript.
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The animal study was reviewed and approved by Animal Ethical and Welfare Committee of Zhejiang Chinese Medical University (Approval Number: No. SYXK (Zhejiang) 2018-0012).
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Chen, W., Liu, Q., Huang, Z. et al. Cucurbitacin C as an effective anti-cancer agent: unveiling its potential role against cholangiocarcinoma and mechanistic insights. J Cancer Res Clin Oncol 149, 13123–13136 (2023). https://doi.org/10.1007/s00432-023-05188-x
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DOI: https://doi.org/10.1007/s00432-023-05188-x