Targeted β-catenin ubiquitination and degradation by multifunctional stapled peptides

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Aberrant Wnt signaling pathway activation is common in many cancers.
• Increased β-catenin levels, due to impaired degradation, drive oncogenesis.
• Targeting β-catenin is a promising strategy for Wnt-dependent cancers.

Purpose of the Study:

• To develop a novel therapeutic strategy targeting β-catenin degradation.
• To utilize multifunctional stapled peptides to recruit E3 ubiquitin ligase to β-catenin.
• To investigate the potential of these peptides as research tools and drug candidates.

Main Methods:

• Design and synthesis of multifunctional stapled peptides linking β-catenin and MDM2 binding moieties.
• In vitro assessment of peptide-induced β-catenin poly-ubiquitination.
• In cellulo evaluation of peptide efficacy in colorectal cancer cells (SW480).
• Luciferase reporter assays to measure Wnt signaling pathway activity.

Main Results:

• Multifunctional stapled peptides successfully recruited MDM2 to β-catenin in vitro.
• Peptides induced poly-ubiquitination and subsequent degradation of β-catenin in cancer cells.
• Dose-dependent reduction in endogenous β-catenin levels was observed.
• Suppression of β-catenin-mediated gene expression via the Wnt pathway was confirmed.

Conclusions:

• Multifunctional stapled peptides effectively degrade β-catenin by hijacking the ubiquitin-proteasome system.
• These peptides serve as valuable tools for studying the Wnt pathway.
• The developed peptides show potential as therapeutic leads for Wnt-dependent cancers.