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

Yi Qu1,2,3, Jan Roger Olsen1, Xing Yuan4

  • 1Department of Clinical Science, University of Bergen, Bergen, Norway.

Nature Chemical Biology
|October 31, 2017
PubMed

Insights

Nitazoxanide (NTZ), an antiparasitic drug, inhibits Wnt/β-catenin signaling in colon cancer by targeting PAD2. This drug promotes β-catenin degradation, offering a potential new cancer therapy for Wnt pathway mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Wnt/β-catenin signaling is crucial for tumor progression and frequently activated in colorectal cancer.
  • Current therapies targeting this pathway are limited, despite its significance.

Purpose of the Study:

  • To identify novel therapeutic agents targeting the Wnt pathway in colorectal cancer.
  • To investigate the mechanism of action of nitazoxanide (NTZ) in Wnt signaling inhibition.

Main Methods:

  • Chemoproteomic approaches were used to identify the molecular target of NTZ.
  • Functional studies involved gene knockout and assessment of β-catenin levels and activity.
  • Colon cancer cell lines with Wnt pathway activation were utilized.

Main Results:

  • Nitazoxanide (NTZ) was identified as an inhibitor of Wnt signaling, independent of APC mutations.
  • Peptidyl arginine deiminase 2 (PAD2) was identified as the functional target of NTZ.
  • NTZ treatment increased β-catenin deamination (citrullination) and degradation, disrupting its transcriptional activity.
  • Knockout of PAD2 or β-catenin conferred resistance to NTZ in colon cancer cells.

Conclusions:

  • Nitazoxanide (NTZ) effectively inhibits Wnt/β-catenin signaling by targeting PAD2 and promoting β-catenin degradation.
  • NTZ represents a potential therapeutic strategy for cancers with Wnt pathway mutations.
  • Modulating β-catenin citrullination is a viable approach for cancer treatment.

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