Bruceine D inhibits hepatocellular carcinoma growth by targeting β-catenin/jagged1 pathways

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) presents high mortality with limited therapeutic options.
• Aberrant activation of Wnt and Notch signaling pathways drives liver carcinogenesis and progression.

Purpose of the Study:

• To identify novel therapeutic agents targeting Wnt and Notch signaling in HCC.
• To investigate the inhibitory effects of bruceine D (BD) on HCC growth and its synergistic potential with sorafenib.

Main Methods:

• Utilized an RBP-Jκ-dependent luciferase-reporter system to screen for Notch inhibitors.
• Evaluated the efficacy of BD in inhibiting liver tumor growth in murine HCC models.
• Assessed the molecular mechanisms underlying BD's action, including its effect on β-catenin and Jagged1 expression.

Main Results:

• Identified bruceine D (BD) as a potent Notch inhibitor.
• BD significantly inhibited liver tumor growth and demonstrated synergistic effects with sorafenib in HCC models.
• Mechanistically, BD promotes proteasomal degradation of β-catenin, reducing its nuclear accumulation and disrupting Wnt/β-catenin-dependent transcription of Jagged1.

Conclusions:

• Bruceine D is a novel Wnt/Notch crosstalk inhibitor with significant anti-HCC activity.
• BD enhances the therapeutic efficacy of sorafenib, presenting a promising combination therapy for HCC treatment.
• These findings hold high clinical impact for advancing HCC therapeutics.