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Daurisoline inhibits pancreatic cancer progression by direct binding to PPARα and blocking its
Dongchao Xu1, Yuanling Zhu2, Wuhan Ye3
1Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou 310006, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310000, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310006, China.
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.
Insights
Daurisoline (DAU) inhibits pancreatic cancer progression by targeting the PPARα and JAK2/STAT3 pathway. It suppresses cell growth and invasion by preventing PPARα ubiquitination, offering a new therapeutic strategy for pancreatic cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Pancreatic cancer (PC) has a high mortality rate with limited treatment options.
- Daurisoline (DAU), a natural alkaloid, shows antitumor potential, but its mechanism is unclear.
Purpose of the Study:
- To evaluate Daurisoline's (DAU) inhibitory effects on pancreatic cancer (PC).
- To elucidate the mechanisms underlying DAU's action, focusing on the PPARα and JAK2/STAT3 pathway.
Main Methods:
- Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed.
- Bioinformatics analysis identified molecular targets.
- PPARα lentiviral transduction and STAT3 activator treatments investigated pathway roles.
- Coimmunoprecipitation assays examined DAU's effect on PPARα ubiquitination.
Main Results:
- DAU suppressed PC cell proliferation, migration, and invasion in a dose- and time-dependent manner.
- DAU induced G1 cell cycle arrest and apoptosis.
- DAU increased PPARα expression, suppressed JAK2/STAT3 signaling, and inhibited PPARα ubiquitination by blocking Trim63 interaction.
Conclusions:
- DAU inhibits pancreatic cancer progression by preventing PPARα ubiquitination and suppressing the JAK2/STAT3 pathway.
- DAU presents a novel therapeutic strategy for pancreatic cancer via ubiquitination pathway modulation.
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