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Oncotarget. 2017 May 9;8(19):31842-31855. doi: 10.18632/oncotarget.16252.

Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction.

Author information

1
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.
2
Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul 03722, Korea.
3
Department of Systems Biology and Division of Life Science, Yonsei University, Seoul 03722, Korea.
4
Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang 10408, Korea.

Abstract

The epithelial-mesenchymal transition (EMT) is implicated in tumorigenesis and cancer progression, and canonical Wnt signaling tightly controls Snail, a key transcriptional repressor of EMT. While the suppression of canonical Wnt signaling and EMT comprises an attractive therapeutic strategy, molecular targets for small molecules reverting Wnt and EMT have not been widely studied. Meanwhile, the anti-helminthic niclosamide has been identified as a potent inhibitor of many oncogenic signaling pathways although its molecular targets have not yet been clearly identified. In this study, we show that niclosamide directly targets Axin-GSK3 interaction, at least in part, resulting in suppression of Wnt/Snail-mediated EMT. In vitro and in vivo, disruption of Axin-GSK3 complex by niclosamide induces mesenchymal to epithelial reversion at nM concentrations, accompanied with suppression of the tumorigenic potential of colon cancer. Niclosamide treatment successfully attenuates Snail abundance while increasing E-cadherin abundance in xenograft tumor. Notably, oral administration of niclosamide significantly suppressed adenoma formation in an APC-MIN mice model, indicating that niclosamide is an effective therapeutic for familial adenomatosis polyposis (FAP) patients. In this study, we identified a novel target to control the canonical Wnt pathway and Snail-mediated EMT program, and discovered a repositioned therapeutics for FAP patients.

KEYWORDS:

Axin-GSK3 interaction; Wnt signaling; epithelial-mesenchymal transition (EMT); familial adenomatosis polyposis (FAP); niclosamide

PMID:
28418862
PMCID:
PMC5458252
DOI:
10.18632/oncotarget.16252
[Indexed for MEDLINE]
Free PMC Article

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