Broussoflavonol B induces S-phase arrest and apoptosis in pancreatic cancer cells by modulating the cell cycle checkpoint through inhibition of the AURKA/PLK1 pathway.
HyokChol Choe, Zhen Wang, Jianhua Huang, Yutong Yang, Zhihao Zhao, HyonSu Jo, HyonU Pak, Tanveer Ali, Kaiyue Ding, Junnan Ma, Lingzhi Li, Dong Shang, Lin Zhang
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引用次数: 0
Abstract
Background: Broussoflavonol B (Bf-B), a flavonoid compound identified in the roots of Daphne giraldii Nitsche, has been extensively investigated for its potential anti-inflammatory, antioxidant, and anticancer properties. However, the precise mechanism underlying the regulation of AURKA/PLK1 pathway-mediated cell cycle arrest by Bf-B in pancreatic cancer remains poorly understood.
Purpose: The objective of this study was to investigate the inhibitory effect of Bf-B on pancreatic ductal adenocarcinoma (PDAC) and its underlying mechanism.
Methods: A CCK8 assay was conducted to identify the flavonoids with the highest inhibitory activity against PANC-1, the pancreatic cancer cell line among the 25 flavonoids. Through bioinformatics analysis and molecular docking, the pathogenic targets of pancreatic cancer and flavonoid-related targets were explored, and the key targets and signaling pathways of drug intervention in pancreatic cancer were analyzed. The viability and migration ability of pancreatic cancer cells were assessed following treatment with Bf-B via the CCK8, colony formation, and wound healing assays. The cell cycle distribution and cell apoptosis were analyzed through flow cytometry and Hoechst staining. Western blotting and qPCR were employed to investigate the expression of relevant proteins and genes. For in vivo experiments, we employed a xenograft mouse model to evaluate the anticancer efficacy of Bf-B. Immunohistochemistry and immunofluorescence assays were employed to investigate the expression of relevant proteins.
Results: In this study, the structure‒activity relationships of 25 flavonoids were evaluated. The results demonstrated that Bf-B with diisopentenyl has potent cytotoxic effects on PANC-1 cancer cells. AURKA, PLK1, and MET might serve as key targets for Bf-B inhibition of disease progression in PDAC patients. The results demonstrated that Bf-B inhibits the proliferation and migration of PANC-1 and BXPC-3 cells and induces cell cycle S-phase arrest, apoptosis, and DNA damage. Moreover, the results of western blot and qPCR experiments indicated that Bf-B exerts anticancer effects by downregulating the expression of the genes encoding AURKA/PLK1, the cell cycle checkpoint kinase ATR/CHK1/CDC25C, and Cyclin B1/CDK1 signaling pathway-related proteins and upregulating the expression of PP53, P21, and histone H2A. XS139ph expression. In xenograft-bearing mice, AURKA/PLK1 expression was reduced in a dose-dependent manner, accompanied by an increase in histone H2A. XS139ph expression.
Conclusion: Bf-B might be a potent therapeutic agent for pancreatic cancer because of its ability to suppress the expression of AURKA/PLK1.
期刊介绍：
Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques.
The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors.
Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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