KMID : 0624620160490090455
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BMB Reports 2016 Volume.49 No. 9 p.455 ~ p.456
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Simultaneous destabilization of ¥â-catenin and Ras via targeting of the axin-RGS domain as a potential therapeutic strategy for colorectal cancer
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Cha Pu-Hyeon
Choi Kang-Yell
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Abstract
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Mutations of APC and KRAS are frequently observed in human CRCs and the Wnt/¥â-catenin and Ras pathways are consequently activated in a significant proportion of CRC patients. Mutations in these two genes are also known to synergistically induce progression of CRCs. Through a series of studies, we have demonstrated that inhibition of the Wnt/¥â-catenin signaling pathway negatively regulates Ras stability, therefore, Ras abundance is increased together with ¥â-catenin in both mice and human CRCs harboring APC mutations. In a recent study, we identified KY1220, a small molecule that simultaneously degrades ¥â-catenin and Ras by inhibition of the Wnt/¥â-catenin pathway, and obtained its derivative KYA1797K, which has improved activity and solubility. We found that KYA1797K binds the RGS domain of axin and enhances the binding affinity of ¥â-catenin or Ras with the ¥â-catenin destruction complex components, leading to simultaneous destabilization of ¥â-catenin and Ras via GSK3¥â activation. By using both in vitro and in vivo studies, we showed that KYA1797K suppressed the growth of CRCs harboring APC and KRAS mutations through destabilization of ¥â-catenin and Ras. Therefore, our findings indicate that the simultaneous destabilization of ¥â-catenin and Ras via targeting axin may serve as an effective strategy for inhibition of CRCs.
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KEYWORD
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¥â-catenin, Colorectal cancer, Ras, Small molecule, Wnt signaling
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