Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3
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Sung Yong Ahn1,*, Ji Hye Yang1,*, Nam Hee Kim1, Kyungro Lee2,3, Yong Hoon Cha1, Jun Seop Yun1, Hee Eun Kang1, Yoonmi Lee1, Jiwon Choi2,3, Hyun Sil Kim1, Jong In Yook1
1Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea
2Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul 03722, Korea
3Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
*These authors have contributed equally to this work
Hyun Sil Kim, email: firstname.lastname@example.org
Jong In Yook, email: email@example.com
Keywords: niclosamide, Ras oncogene, GSK-3, epithelial-mesenchymal transition (EMT)
Received: November 23, 2016 Accepted: February 23, 2017 Published: March 16, 2017
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.
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