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Small molecule-induced simultaneous destabilization of β-catenin and RAS is an effective molecular strategy to suppress stemness of colorectal cancer cells

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Authors
Cho, Yong-Hee; Ro, Eun Ji; Yoon, Jeong-Su; Kwak, Dong-Kyu; Cho, Jaebeom; Kang, Dong Woo; Lee, Ho-Young; Choi, Kang-Yell
Issue Date
2020-03-06
Publisher
BMC
Citation
Cell Communication and Signaling. 2020 Mar 06;18(1):38
Keywords
Cancer stem cellsβ-CateninRASDestabilizationKYA1797K
Abstract
Background
Cancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood.

Methods
Gene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set. The therapeutic effects of destabilization of β-catenin and RAS were tested by treatment of small molecule KYA1797K using CRC patient derived cells.

Results
Treatment with KYA1797K, a small molecule that destabilizes both β-catenin and RAS via Axin binding, effectively suppresses the stemness of CSCs as shown in CRC spheroids and small intestinal tumors of ApcMin/+/K-RasG12DLA2 mice. Moreover, KYA1797K also suppresses the stemness of cells in CRC patient avatar model systems, such as patient-derived tumor organoids (PDTOs) and patient-derived tumor xenograft (PDTX).

Conclusion
Our results suggest that destabilization of both β-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells.
ISSN
1478-811X
Language
English
URI
https://hdl.handle.net/10371/168727
DOI
doi.org/10.1186/s12964-020-0519-z
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Journal Papers (저널논문_약학과)
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