Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction
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Sung Yong Ahn1,*, Nam Hee Kim1,*, Kyungro Lee2,3, Yong Hoon Cha1, Ji Hye Yang1, So Young Cha1, Eunae Sandra Cho1, Yoonmi Lee1, Jeong Seok Cha3, Hyun Soo Cho3, Yoon Jeon4, Young-Su Yuk1, Suebean Cho1, Kyoung Tai No2,3, Hyun Sil Kim1, Ho Lee4, Jiwon Choi2, Jong In Yook1
1Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea
2Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul 03722, Korea
3Department of Systems Biology and Division of Life Science, Yonsei University, Seoul 03722, Korea
4Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang 10408, Korea
*These authors have contributed equally to this work
Jong In Yook, email: email@example.com
Jiwon Choi, email: firstname.lastname@example.org
Ho Lee, email: email@example.com
Keywords: niclosamide, epithelial-mesenchymal transition (EMT), Axin-GSK3 interaction, Wnt signaling, familial adenomatosis polyposis (FAP)
Received: November 22, 2016 Accepted: February 20, 2017 Published: March 16, 2017
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.
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