Miclxin是一种新型的MIC60抑制剂，可通过线粒体应激诱导β-Catenin突变肿瘤细胞凋亡。,ACS Chemical Biology

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Miclxin是一种新型的MIC60抑制剂，可通过线粒体应激诱导β-Catenin突变肿瘤细胞凋亡。
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-06-25 , DOI: 10.1021/acschembio.0c00381
Hiroaki Ikeda _{1,

2} , Makoto Muroi ₃ , Yasumitsu Kondoh ₃ , Shumpei Ishikawa ₄ , Hideaki Kakeya ₂ , Hiroyuki Osada ₃ , Masaya Imoto ₁

Affiliation

Wnt信号通路调节多种细胞过程。β-连环蛋白是该途径的主要成分之一，在其中起主要作用。尽管已经确定β-连环蛋白在多种肿瘤中发生突变，但是目前没有靶向β-连环蛋白的有效治疗剂。在这项研究中，我们搜索了针对突变β-连环蛋白的化合物，并发现了DS37262926（miclxin）。Miclxin表现出β连环蛋白突变的HCT116细胞和同基因的HCT116（β连环蛋白依赖的细胞凋亡CTNNB1 Δ45/ - ）细胞; 但是，在等基因HCT116（CTNNB1+/-）单元格。使用固定有微调蛋白的珠子，将MIC60（线粒体接触部位和protein组织系统（MICOS）复合体的主要成分之一）鉴定为微调蛋白的靶蛋白。我们揭示了由miclxin引起的MIC60功能障碍以突变的β-catenin依赖性方式诱导线粒体应激反应。线粒体应激反应的激活导致Bcl-2的下调，导致线粒体膜电位的严重丧失和随后的凋亡诱导因子依赖性凋亡。我们的发现表明，靶向MIC60是一种潜在的策略，通过这种策略，可以通过以突变的β-catenin依赖性方式诱导严重的线粒体损伤来杀死肿瘤细胞。

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Miclxin, a Novel MIC60 Inhibitor, Induces Apoptosis via Mitochondrial Stress in β-Catenin Mutant Tumor Cells.

The Wnt signaling pathway regulates diverse cellular processes. β-Catenin is one of the major components of this pathway, in which it plays a main role. Although it has been established that β-catenin is mutated in a wide variety of tumors, there are currently no effective therapeutic agents that target β-catenin. In this study, we searched for the compound that targets mutant β-catenin and found DS37262926 (miclxin). Miclxin exhibited β-catenin-dependent apoptosis in β-catenin-mutated HCT116 cells and isogenic HCT116 (CTNNB1 Δ45/−) cells; however, this effect was not observed in isogenic HCT116 (CTNNB1 +/−) cells. Using miclxin-immobilized beads, MIC60, one of the major components of the mitochondrial contact site and cristae organizing system (MICOS) complex, was identified as a target protein of miclxin. We revealed that MIC60 dysfunction caused by miclxin induced a mitochondrial stress response in a mutant β-catenin-dependent manner. Activation of the mitochondrial stress response was responsible for the downregulation of Bcl-2, leading to severe loss of mitochondrial membrane potential and subsequent apoptosis-inducing factor-dependent apoptosis. Our findings suggest that targeting MIC60 is a potential strategy with which tumor cells can be killed through induction of severe mitochondrial damage in a mutant β-catenin-dependent manner.

更新日期：2020-08-21

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