Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction
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, molecu...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458252/ https://www.ncbi.nlm.nih.gov/pubmed/28418862 http://dx.doi.org/10.18632/oncotarget.16252 |
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author | Ahn, Sung Yong Kim, Nam Hee Lee, Kyungro Cha, Yong Hoon Yang, Ji Hye Cha, So Young Cho, Eunae Sandra Lee, Yoonmi Cha, Jeong Seok Cho, Hyun Soo Jeon, Yoon Yuk, Young-Su Cho, Suebean No, Kyoung Tai Kim, Hyun Sil Lee, Ho Choi, Jiwon Yook, Jong In |
author_facet | Ahn, Sung Yong Kim, Nam Hee Lee, Kyungro Cha, Yong Hoon Yang, Ji Hye Cha, So Young Cho, Eunae Sandra Lee, Yoonmi Cha, Jeong Seok Cho, Hyun Soo Jeon, Yoon Yuk, Young-Su Cho, Suebean No, Kyoung Tai Kim, Hyun Sil Lee, Ho Choi, Jiwon Yook, Jong In |
author_sort | Ahn, Sung Yong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5458252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-54582522017-06-08 Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction Ahn, Sung Yong Kim, Nam Hee Lee, Kyungro Cha, Yong Hoon Yang, Ji Hye Cha, So Young Cho, Eunae Sandra Lee, Yoonmi Cha, Jeong Seok Cho, Hyun Soo Jeon, Yoon Yuk, Young-Su Cho, Suebean No, Kyoung Tai Kim, Hyun Sil Lee, Ho Choi, Jiwon Yook, Jong In Oncotarget Research Paper 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. Impact Journals LLC 2017-03-16 /pmc/articles/PMC5458252/ /pubmed/28418862 http://dx.doi.org/10.18632/oncotarget.16252 Text en Copyright: © 2017 Ahn et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Ahn, Sung Yong Kim, Nam Hee Lee, Kyungro Cha, Yong Hoon Yang, Ji Hye Cha, So Young Cho, Eunae Sandra Lee, Yoonmi Cha, Jeong Seok Cho, Hyun Soo Jeon, Yoon Yuk, Young-Su Cho, Suebean No, Kyoung Tai Kim, Hyun Sil Lee, Ho Choi, Jiwon Yook, Jong In Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction |
title | Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction |
title_full | Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction |
title_fullStr | Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction |
title_full_unstemmed | Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction |
title_short | Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction |
title_sort | niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting axin-gsk3 interaction |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458252/ https://www.ncbi.nlm.nih.gov/pubmed/28418862 http://dx.doi.org/10.18632/oncotarget.16252 |
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