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.
Bibliographical noteFunding Information:
We thank E. Tunkle for preparation of the manuscript and K.Y. Kim for statistical analysis. This work was supported by grants from the National Research Foundation of Korea (NRF-2012M3A9B2052523, NRF-2014R1A2A1A05004670, NRF-2014M3C1A3051 476, NRF-2016R1E1A1A01942724) funded by the Korea government (MSIP), a grant from the National Research Foundation of Korea (NRF-2014R1A6A3A04055110) funded by the Korea government (MOE), and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1420310).
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