Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:81727-81740. https://doi.org/10.18632/oncotarget.13172

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Abstract

Yong-Hee Cho1,2, Pu-Hyeon Cha1,2, Saluja Kaduwal1,2, Jong-Chan Park1,2, Sang-Kyu Lee1,2, Jeong-Soo Yoon1,2, Wookjin Shin1,2, Hyuntae Kim1,2, Eun Ji Ro1,2, Kyung-Hwa Koo1,2, Ki-Sook Park3, Gyoonhee Han1,2, Kang-Yell Choi1,2

1Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea

2Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea

3College of Medicine, East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Korea

Correspondence to:

Kang-Yell Choi, email: [email protected]

Keywords: Apc mutation, K-Ras mutation, tumor budding, metastatic colorectal cancer, Ras destabilizer

Received: August 20, 2016     Accepted: October 19, 2016     Published: November 07, 2016

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 APCMin/+/K-RasG12DLA2 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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