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.
Keywords:
Apc mutation; K-Ras mutation; Ras destabilizer; metastatic colorectal cancer; tumor budding.
MeSH terms
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Actin Cytoskeleton / drug effects
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Actin Cytoskeleton / metabolism
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Actin Cytoskeleton / pathology
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / secondary
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Movement / drug effects*
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Cell Proliferation / drug effects
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Disease Models, Animal
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Epithelial-Mesenchymal Transition / drug effects
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Genes, APC
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HEK293 Cells
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Humans
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation
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Neoplasm Invasiveness
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Protein Stability
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Proteolysis
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism*
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Thiohydantoins / pharmacology*
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Time Factors
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Wnt Signaling Pathway / drug effects*
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Antineoplastic Agents
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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KRAS protein, human
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KY1220
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Thiohydantoins
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beta Catenin
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)