KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer.
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.
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Yong-Hee
YH
Cho
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Pu-Hyeon
PH
Cha
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Saluja
S
Kaduwal
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Jong-Chan
JC
Park
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Sang-Kyu
SK
Lee
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Jeong-Soo
JS
Yoon
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Wookjin
W
Shin
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Hyuntae
H
Kim
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Eun Ji
EJ
Ro
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Kyung-Hwa
KH
Koo
College of Medicine, East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Korea.
Ki-Sook
KS
Park
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Gyoonhee
G
Han
Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Kang-Yell
KY
Choi
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D017491:Genes, APC; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009361:Neoplasm Invasiveness; D055550:Protein Stability; D059748:Proteolysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D013867:Thiohydantoins / Q000494:pharmacology*; D013997:Time Factors; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C117307:KRAS protein, human; C000617986:KY1220; D013867:Thiohydantoins; D051176:beta Catenin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
Apc mutation; K-Ras mutation; Ras destabilizer; metastatic colorectal cancer; tumor budding