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.

Abstract

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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