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

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

Author information

1
Department of Clinical Science, University of Bergen, Bergen, Norway.
2
Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
3
Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
4
Department of Phytochemistry, College of Pharmacy, Second Military Medical University, Shanghai, P.R. China.
5
Department of Dermatology, University of Zürich, University of Zürich Hospital, Zürich, Switzerland.
6
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.
7
Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
8
Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.

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.

PMID:
29083417
DOI:
10.1038/nchembio.2510
[Indexed for MEDLINE]

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