Chlorquinaldol targets the β-catenin and T-cell factor 4 complex and exerts anti-colorectal cancer activity

Pharmacol Res. 2020 Sep:159:104955. doi: 10.1016/j.phrs.2020.104955. Epub 2020 May 30.

Abstract

Aberrant activation of Wnt signaling plays a critical role in the initiation and progression of colorectal cancer (CRC). Chlorquinaldol (CQD) is a topical antimicrobial agent used to treat skin infections. Little is known about the anticancer activity of CQD and its underlying mechanisms. In this study, CQD was demonstrated to inhibit Wnt/β-catenin signaling through targeting the downstream part of this pathway. The results showed that CQD could inhibit the acetylation of β-catenin and disrupt the interaction of β-catenin with T-cell factor 4 (TCF4), leading to reduced binding of β-catenin to the promoters of Wnt target genes and downregulation of the expression of these target genes. Moreover, treatment with CQD suppressed the proliferation, migration, invasion and stemness of CRC cells. In APCmin/+ mice and CRC cell xenografts, administration of CQD suppressed tumor growth and the expression of Wnt target genes c-Myc and Leucine-rich G protein-coupled receptor-5 (LGR5). These results strongly suggest that CQD may be a promising therapeutic agent in the treatment of CRC.

Keywords: 8-Hydroxyquinoline; Colorectal cancer stem cell; Transcriptional regulation; Wnt/β-catenin signaling; β-catenin acetylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chlorquinaldol / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, APC
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, Transgenic
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Protein Binding
  • Protein Processing, Post-Translational
  • Transcription Factor 7-Like 2 Protein / metabolism*
  • Tumor Burden / drug effects
  • Wnt Signaling Pathway
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, human
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin
  • Chlorquinaldol