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Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3

Authors
 Sung Yong Ahn  ;  Ji Hye Yang  ;  Nam Hee Kim  ;  Kyungro Lee  ;  Yong Hoon Cha  ;  Jun Seop Yun  ;  Hee Eun Kang  ;  Yoonmi Lee  ;  Jiwon Choi  ;  Hyun Sil Kim  ;  Jong In Yook 
Citation
 Oncotarget, Vol.8(19) : 31856-31863, 2017 
Journal Title
 Oncotarget 
Issue Date
2017
MeSH
Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/drug effects* ; Cell Transformation, Neoplastic/genetics* ; Cell Transformation, Neoplastic/metabolism* ; Disease Models, Animal ; Enzyme Activation/drug effects ; Genes, ras* ; Glycogen Synthase Kinase 3/metabolism* ; Humans ; Models, Biological ; Mutation ; Niclosamide/pharmacology* ; Xenograft Model Antitumor Assays
Keywords
GSK-3 ; Ras oncogene ; epithelial-mesenchymal transition (EMT) ; niclosamide
Abstract
Despite the importance of Ras oncogenes as a therapeutic target in human cancer, their 'undruggable' tertiary structures limit the effectiveness of anti-Ras drugs. Canonical Wnt signaling contributes to Ras activity by glycogen synthase kinase 3 (GSK-3)-dependent phosphorylation at the C-terminus and subsequent degradation. In the accompanying report, we show that the anti-helminthic niclosamide directly binds to GSK-3 and inhibits Axin functions in colon cancer cells, with reversion of Snail-mediated epithelial-mesenchymal transition. In this study, we report that niclosamide effectively suppresses Ras and nuclear NFAT activities regardless of the mutational status of Ras at nM levels. Mechanistically, niclosamide increased endogenous GSK-3 activity, shortening the half-life of mutant Ras. Further, niclosamide activates Raf-1 kinase inhibitory protein, a downstream target of Snail repressor. Niclosamide treatment attenuates Ras-induced oncogenic potential in vitro and in vivo. These findings provide a clinically available repositioned Ras inhibitor as well as a novel strategy for inhibiting the Ras via GSK-3.
Files in This Item:
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DOI
10.18632/oncotarget.16255
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral and Maxillofacial Surgery (구강악안면외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
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
이윤미(Lee, Yoon Mi)
차용훈(Cha, Yong Hoon) ORCID logo https://orcid.org/0000-0003-1761-3260
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/153810
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