An Intrinsically Labile α-helix Abutting the BCL9-binding Site of β-catenin Is Required for Its Inhibition by Carnosic Acid

Nat Commun. 2012 Feb 21;3:680. doi: 10.1038/ncomms1680.

Abstract

Wnt/β-catenin signalling controls development and tissue homeostasis. Moreover, activated β-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic β-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of β-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional β-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile α-helix (H1) amino-terminally abutting the BCL9-binding site in β-catenin. Similarly, in colorectal cancer cells with hyperactive β-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of β-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of β-catenin, which can be exploited for destabilization of oncogenic β-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abietanes / pharmacology*
  • Binding Sites
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy
  • Crystallography, X-Ray
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Neoplasm Proteins / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Plant Extracts / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • Rosmarinus
  • Signal Transduction
  • Transcription Factors
  • Wnt Proteins / metabolism
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / chemistry*
  • beta Catenin / metabolism

Substances

  • Abietanes
  • BCL9 protein, human
  • Neoplasm Proteins
  • Plant Extracts
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • Proteasome Endopeptidase Complex
  • salvin