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

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 Snailmediated EMT program, and discovered a repositioned therapeutics for FAP patients.

Original languageEnglish
Pages (from-to)31842-31855
Number of pages14
JournalOncotarget
Volume8
Issue number19
DOIs
Publication statusPublished - 2017 Jan 1

Fingerprint

Niclosamide
Epithelial-Mesenchymal Transition
Therapeutics
Wnt Signaling Pathway
Snails
Cadherins
Heterografts
Adenoma
Colonic Neoplasms
Oral Administration
Neoplasms
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Ahn, S. Y., Kim, N. H., Lee, K., Cha, Y. H., Yang, J. H., Cha, S. Y., ... Yook, J. I. (2017). Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction. Oncotarget, 8(19), 31842-31855. https://doi.org/10.18632/oncotarget.16252
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. In: Oncotarget. 2017 ; Vol. 8, No. 19. pp. 31842-31855.
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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 Snailmediated EMT program, and discovered a repositioned therapeutics for FAP patients.",
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Ahn, SY, Kim, NH, Lee, K, Cha, YH, Yang, JH, Cha, SY, Cho, ES, Lee, Y, Cha, JS, Cho, HS, Jeon, Y, Yuk, YS, Cho, S, No, KT, Kim, HS, Lee, H, Choi, J & Yook, JI 2017, 'Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction', Oncotarget, vol. 8, no. 19, pp. 31842-31855. https://doi.org/10.18632/oncotarget.16252

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.

In: Oncotarget, Vol. 8, No. 19, 01.01.2017, p. 31842-31855.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction

AU - Ahn, Sung Yong

AU - Kim, Nam Hee

AU - Lee, Kyungro

AU - Cha, Yong Hoon

AU - Yang, Ji Hye

AU - Cha, So Young

AU - Cho, Eunae Sandra

AU - Lee, Yoonmi

AU - Cha, Jeong Seok

AU - Cho, Hyun Soo

AU - Jeon, Yoon

AU - Yuk, Young Su

AU - Cho, Suebean

AU - No, Kyoung Tai

AU - Kim, Hyun Sil

AU - Lee, Ho

AU - Choi, Jiwon

AU - Yook, Jong In

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

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