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

Sung Yong Ahn, Nam Hee Kim, Kyungro Lee, Yong Hoon Cha, Ji Hye Yang, So Young Cha, Eunae Sandra Cho, Yoonmi Lee, Jeong Seok Cha, Hyun Soo Cho, Yoon Jeon, Young Su Yuk, Suebean Cho, Kyoung Tai No, Hyun Sil Kim, Ho Lee, Jiwon Choi, Jong In Yook

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10 Citations (Scopus)

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 Snailmediated EMT program, and discovered a repositioned therapeutics for FAP patients.

Original languageEnglish
Pages (from-to)31842-31855
Number of pages14
JournalOncotarget
Volume8
Issue number19
DOIs
Publication statusPublished - 2017 Jan 1

All Science Journal Classification (ASJC) codes

  • Oncology

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    Ahn, S. Y., Kim, N. H., Lee, K., Cha, Y. H., Yang, J. H., Cha, S. Y., Cho, E. S., Lee, Y., Cha, J. S., Cho, H. S., Jeon, Y., Yuk, Y. S., Cho, S., No, K. T., Kim, H. S., Lee, H., Choi, J., & Yook, J. I. (2017). Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction. Oncotarget, 8(19), 31842-31855. https://doi.org/10.18632/oncotarget.16252