Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Daurisoline inhibits pancreatic cancer progression by direct binding to PPARα and blocking its ubiquitination-mediated degradation.
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Xu Dongchao, Zhu Yuanling, Ye Wuhan, Yu Yuhua, Wang Xuehui, Xu Chenshan, Jiang Ke, Chen Wangyang, Zhang Xiaofeng, Shen Hongzhang
Аннотация
BACKGROUND: Pancreatic cancer (PC) is well known for its high lethality, and limited therapeutic options are currently available. Daurisoline (DAU), a bisbenzylisoquinoline alkaloid isolated from Menispermum dauricum DC., has demonstrated antitumor effects in several cancers, although its precise mechanism of action remains unclear.
PURPOSE: This study evaluated the DAU-mediated inhibition of pancreatic cancer and the mechanisms responsible.
METHODS: DAU's inhibitory effects on PC cells were measured through EdU, CCK-8, wound healing, Transwell, and flow cytometry assays. Bioinformatics analysis revealed molecular expression alterations between PC cells treated with or without DAU. The roles of the PPARα and JAK2/STAT3 pathway in DAU-mediated PC suppression were investigated via PPARα lentiviral transduction and STAT3 activator treatment, respectively. Coimmunoprecipitation assays were performed to confirm the impact of DAU on PPARα ubiquitination and identify the specific ubiquitin ligase involved.
RESULTS: Our findings revealed that DAU suppresses the proliferation of pancreatic cancer cells in a time- and dose-dependent manner while also inhibiting cell migration and invasion. Additionally, DAU arrests the cell cycle at the G1 phase and induces apoptosis. Mechanistically, bioinformatics analysis combined with experimental validation demonstrated that DAU binds to PPARα, increases its expression, and subsequently suppresses JAK2/STAT3 signaling. Notably, DAU competitively blocks the Trim63-PPARα interaction by binding to PPARα, thereby suppressing PPARα ubiquitination to increase its protein stability.
CONCLUSION: DAU inhibits the JAK2/STAT3 signaling pathway by preventing PPARα ubiquitination, thereby suppressing the progression of PC cells. This research provides a new therapeutic strategy and a promising compound for treatment of PC through suppression of the ubiquitination pathway.
PURPOSE: This study evaluated the DAU-mediated inhibition of pancreatic cancer and the mechanisms responsible.
METHODS: DAU's inhibitory effects on PC cells were measured through EdU, CCK-8, wound healing, Transwell, and flow cytometry assays. Bioinformatics analysis revealed molecular expression alterations between PC cells treated with or without DAU. The roles of the PPARα and JAK2/STAT3 pathway in DAU-mediated PC suppression were investigated via PPARα lentiviral transduction and STAT3 activator treatment, respectively. Coimmunoprecipitation assays were performed to confirm the impact of DAU on PPARα ubiquitination and identify the specific ubiquitin ligase involved.
RESULTS: Our findings revealed that DAU suppresses the proliferation of pancreatic cancer cells in a time- and dose-dependent manner while also inhibiting cell migration and invasion. Additionally, DAU arrests the cell cycle at the G1 phase and induces apoptosis. Mechanistically, bioinformatics analysis combined with experimental validation demonstrated that DAU binds to PPARα, increases its expression, and subsequently suppresses JAK2/STAT3 signaling. Notably, DAU competitively blocks the Trim63-PPARα interaction by binding to PPARα, thereby suppressing PPARα ubiquitination to increase its protein stability.
CONCLUSION: DAU inhibits the JAK2/STAT3 signaling pathway by preventing PPARα ubiquitination, thereby suppressing the progression of PC cells. This research provides a new therapeutic strategy and a promising compound for treatment of PC through suppression of the ubiquitination pathway.