Hexachlorophene inhibits Wnt/beta-catenin pathway by promoting Siah-mediated beta-catenin degradation

Mol Pharmacol. 2006 Sep;70(3):960-6. doi: 10.1124/mol.106.024729. Epub 2006 May 30.

Abstract

Aberrant activation of Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) is a critical event in the development of human colon cancer. Thus, Wnt/beta-catenin signaling is an attractive target for the development of anticancer therapeutics. In this study, we identified hexachlorophene as an inhibitor of Wnt/beta-catenin signaling from cell-based small-molecule screening. Hexachlorophene antagonized CRT that was stimulated by Wnt3a-conditioned medium by promoting the degradation of beta-catenin. This degradation pathway is Siah-1 and adenomatous polyposis colidependent, but glycogen synthase kinase-3beta and F-box beta-transducin repeat-containing protein-independent. In addition, hexachlorophene represses the expression of cyclin D1, which is a known beta-catenin target gene, and inhibits the growth of colon cancer cells. Our findings suggest that hexachlorophene attenuates Wnt/beta-catenin signaling through the Siah-1-mediated beta-catenin degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents, Local / pharmacology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Colonic Neoplasms / pathology
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hexachlorophene / chemistry
  • Hexachlorophene / pharmacology*
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Processing, Post-Translational / drug effects*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects*
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt3 Protein
  • Wnt3A Protein
  • beta Catenin / genetics
  • beta Catenin / metabolism*
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • Anti-Infective Agents, Local
  • Nuclear Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • WNT3A protein, human
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Hexachlorophene