KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer

Yong Hee Cho, Pu Hyeon Cha, Saluja Kaduwal, Jong Chan Park, Sang Kyu Lee, Jeong Soo Yoon, Wookjin Shin, Hyuntae Kim, Eun Ji Ro, Kyung Hwa Koo, Ki Sook Park, Gyoonhee Han, Kang Yell Choi

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β- catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APC Min/+ /K-Ras G12D LA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.

Original languageEnglish
Pages (from-to)81727-81740
Number of pages14
JournalOncotarget
Volume7
Issue number49
DOIs
Publication statusPublished - 2016 Jan 1

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Catenins
Wnt Signaling Pathway
Colorectal Neoplasms
Carcinogenesis
Neoplasm Metastasis
Mutation
Apoptosis
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Cho, Yong Hee ; Cha, Pu Hyeon ; Kaduwal, Saluja ; Park, Jong Chan ; Lee, Sang Kyu ; Yoon, Jeong Soo ; Shin, Wookjin ; Kim, Hyuntae ; Ro, Eun Ji ; Koo, Kyung Hwa ; Park, Ki Sook ; Han, Gyoonhee ; Choi, Kang Yell. / KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer. In: Oncotarget. 2016 ; Vol. 7, No. 49. pp. 81727-81740.
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abstract = "APC (80-90{\%}) and K-Ras (40-50{\%}) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β- catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APC Min/+ /K-Ras G12D LA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.",
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Cho, YH, Cha, PH, Kaduwal, S, Park, JC, Lee, SK, Yoon, JS, Shin, W, Kim, H, Ro, EJ, Koo, KH, Park, KS, Han, G & Choi, KY 2016, 'KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer', Oncotarget, vol. 7, no. 49, pp. 81727-81740. https://doi.org/10.18632/oncotarget.13172

KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer. / Cho, Yong Hee; Cha, Pu Hyeon; Kaduwal, Saluja; Park, Jong Chan; Lee, Sang Kyu; Yoon, Jeong Soo; Shin, Wookjin; Kim, Hyuntae; Ro, Eun Ji; Koo, Kyung Hwa; Park, Ki Sook; Han, Gyoonhee; Choi, Kang Yell.

In: Oncotarget, Vol. 7, No. 49, 01.01.2016, p. 81727-81740.

Research output: Contribution to journalArticle

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AU - Cha, Pu Hyeon

AU - Kaduwal, Saluja

AU - Park, Jong Chan

AU - Lee, Sang Kyu

AU - Yoon, Jeong Soo

AU - Shin, Wookjin

AU - Kim, Hyuntae

AU - Ro, Eun Ji

AU - Koo, Kyung Hwa

AU - Park, Ki Sook

AU - Han, Gyoonhee

AU - Choi, Kang Yell

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AB - APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β- catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APC Min/+ /K-Ras G12D LA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.

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