Small molecule promotes β-catenin citrullination and inhibits Wnt signaling in cancer

Nat Chem Biol. 2018 Jan;14(1):94-101. doi: 10.1038/nchembio.2510. Epub 2017 Oct 30.

Abstract

Wnt (wingless)/β-catenin signaling is critical for tumor progression and is frequently activated in colorectal cancer as a result of the mutation of adenomatous polyposis coli (APC); however, therapeutic agents targeting this pathway for clinical use are lacking. Here we report that nitazoxanide (NTZ), a clinically approved antiparasitic drug, efficiently inhibits Wnt signaling independent of APC. Using chemoproteomic approaches, we have identified peptidyl arginine deiminase 2 (PAD2) as the functional target of NTZ in Wnt inhibition. By targeting PAD2, NTZ increased the deamination (citrullination) and turnover of β-catenin in colon cancer cells. Replacement of arginine residues disrupted the transcriptional activity, and NTZ induced degradation of β-catenin. In Wnt-activated colon cancer cells, knockout of either PAD2 or β-catenin substantially increased resistance to NTZ treatment. Our data highlight the potential of NTZ as a modulator of β-catenin citrullination for the treatment of cancer patients with Wnt pathway mutations.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Citrullination
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Gene Knockout Techniques
  • Humans
  • Protein-Arginine Deiminase Type 2
  • Protein-Arginine Deiminases / genetics
  • Protein-Arginine Deiminases / metabolism*
  • Thiazoles / pharmacology*
  • Wnt Signaling Pathway / drug effects*
  • Wnt Signaling Pathway / genetics
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents
  • Thiazoles
  • beta Catenin
  • PADI2 protein, human
  • Protein-Arginine Deiminase Type 2
  • Protein-Arginine Deiminases
  • nitazoxanide

Associated data

  • PubChem-Substance/346398268