title: Simultaneous destabilization of β-catenin and Ras via targeting of the axin-RGS domain as a potential therapeutic strategy for colorectal cancer.
abstract: Mutations of APC and KRAS are frequently observed in human colorectal cancers (CRCs) and the Wnt/β-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/β-catenin signaling pathway negatively regulates Ras stability, therefore, Ras abundance is increased together with β-catenin in both mice and human CRCs harboring adenomatous polyposis coli (APC) mutations. In a recent study, we identified KY1220, a small molecule that simultaneously degrades β-catenin and Ras by inhibition of the Wnt/β-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 β-catenin or Ras with the β-catenin destruction complex components, leading to simultaneous destabilization of β-catenin and Ras via GSK3β 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 β-catenin and Ras. Therefore, our findings indicate that the simultaneous destabilization of β-catenin and Ras via targeting axin may serve as an effective strategy for inhibition of CRCs. [BMB Reports 2016; 49(9): 455-456].
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University and Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
authors.forename: Pu-Hyeon
authors.initials: PH
authors.lastname: Cha
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University and Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D060466:Axin Protein / Q000737:chemistry / Q000378:metabolism*; D015179:Colorectal Neoplasms; D006801:Humans; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D053778:Thiazolidines / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D053778:Thiazolidines; D051176:beta Catenin; D018631:ras Proteins