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

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.

• Authors: Yi Qu, Jan Roger Olsen, Xing Yuan, Phil F Cheng, Mitchell P Levesque, Karl A Brokstad, Paul S Hoffman, Anne Margrete Oyan, Weidong Zhang, Karl-Henning Kalland, Xisong Ke
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 14 Issue 1 Pg. 94-101 (Jan 2018) ISSN: 1552-4469 [Electronic] United States
• PMID: 29083417 (Publication Type: Journal Article)

Chemical References

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

Topics

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