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

Authors
 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 
Citation
 Oncotarget, Vol.8(19) : 31842-31855, 2017 
Journal Title
 Oncotarget 
Issue Date
2017
MeSH
Adenomatous Polyposis Coli/drug therapy ; Adenomatous Polyposis Coli/genetics ; Adenomatous Polyposis Coli/metabolism* ; Animals ; Axin Protein/chemistry ; Axin Protein/metabolism* ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Epithelial-Mesenchymal Transition/drug effects ; Glycogen Synthase Kinase 3/chemistry ; Glycogen Synthase Kinase 3/metabolism* ; Heterografts ; Mice ; Models, Molecular ; Molecular Conformation ; Niclosamide/chemistry ; Niclosamide/pharmacology* ; Protein Binding/drug effects ; Wnt Signaling Pathway/drug effects
Keywords
Axin-GSK3 interaction ; Wnt signaling ; epithelial-mesenchymal transition (EMT) ; familial adenomatosis polyposis (FAP) ; niclosamide
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.
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DOI
10.18632/oncotarget.16252
Appears in Collections:
1. Journal Papers (연구논문) > 2. College of Dentistry (치과대학) > Dept. of Oral and Maxillofacial Surgery (구강악안면외과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실)
1. Journal Papers (연구논문) > 5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소)
1. Journal Papers (연구논문) > 2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실)
Yonsei Authors
김남희(Kim, Nam Hee) ORCID logo https://orcid.org/0000-0002-3087-5276
김현실(Kim, Hyun Sil) ORCID logo https://orcid.org/0000-0003-3614-1764
안성용(Ahn, Sung Yong) ORCID logo https://orcid.org/0000-0002-6029-1853
양지혜(Yang, Ji Hye)
육종인(Yook, Jong In) ORCID logo https://orcid.org/0000-0002-7318-6112
차소영(Cha, So Young)
차용훈(Cha, Yong Hoon)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/153827
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