Simultaneous destabilization of β-catenin and Ras via targeting of the axin-RGS domain as a potential therapeutic strategy for colorectal cancer.
Simultaneous destabilization of β-catenin and Ras via targeting of the axin-RGS domain as a potential therapeutic strategy for colorectal cancer.
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DOI：
10.5483/bmbrep.2016.49.9.125
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发表时间：
2016-09
期刊：
影响因子：
3.8
通讯作者：
Choi KY
中科院分区：
文献类型：
--
作者：
Cha PH;Choi KY
APC和KRAS基因突变在人类结直肠癌中非常常见，因此Wnt/β-catenin和RAS通路在相当比例的结直肠癌患者中被激活。这两个基因的突变也是已知的协同诱导癌进展的因素。通过一系列的研究，我们已经证明抑制Wnt/β-catenin信号通路对RAS的稳定性具有负面调节作用，因此，RAS的丰度与β-catenin一起在携带大肠腺瘤性息肉病突变的小鼠和人类CRC中增加。在最近的一项研究中，我们鉴定了KY1220，一个通过抑制WNT/β-连环蛋白途径同时降解β-连环蛋白和RAS的小分子，并获得了其衍生物KYA1797K，它具有更好的活性和溶解性。我们发现KYA1797K结合了Axin的RGS结构域，并增强了β-连环蛋白或RAS与β-连环蛋白破坏复合体成分的结合亲和力，导致β-连环蛋白和RAS通过β激活而同时失稳。通过体外和体内研究，我们发现KYA1797K通过使β-连环蛋白和RAS失稳来抑制含有APC和KRAS突变的CRC的生长。因此，我们的研究结果表明，通过靶向Axin同时使β-Catenin和RAS失稳，可能是一种有效的抑制癌基因的策略。[BMB报告2016；49(9)：455-456]
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]