Co-targeting translation and proteasome rapidly kills colon cancer cells with mutant RAS/RAF via ER stress.
Co-targeting translation and proteasome rapidly kills colon cancer cells with mutant RAS/RAF via ER stress.
复制标题
共靶向翻译和蛋白酶体通过 ER 应激快速杀死具有突变 RAS/RAF 的结肠癌细胞。
DOI：
10.18632/oncotarget.14063
复制
发表时间：
2017-02-07
期刊：
影响因子：
--
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Li X;Li M;Ruan H;Qiu W;Xu X;Zhang L;Yu J
RAS/RAF突变的结直肠癌是治疗难治性的。不受管制的mRNA翻译已成为癌症治疗的新兴靶点。我们最近报道mTOR抑制剂通过内质网应激和外源性途径诱导凋亡，急性抑制结肠癌细胞和异种移植物中的eIF4F复合物，而突变BRAF600E通过erk介导的Mcl-1稳定导致治疗耐药。在这项研究中，我们证明了其他几种翻译抑制剂也激活内质网应激和外源性凋亡途径。Episilvestrol和Bortezomib联合靶向翻译和蛋白酶体，在培养和小鼠中促进了强烈的内质网应激和突变RAS/RAF结肠癌细胞的快速杀伤。这种组合导致内质膜应激和ATF4/CHOP的显著诱导，随后是DR5-和bax依赖性的凋亡，但出乎意料的是，促生存因子如p-AKT、p-4E-BP1、Mcl-1和eiF4E靶点c-Myc和Bcl-xL的水平保持甚至增加。我们的研究支持，通过诱导破坏性内质网应激，克服与翻译抑制相关的多种耐药机制，靶向不受调节的蛋白酶抑制是治疗晚期结肠癌的一种有希望的方法。
Colorectal cancers with mutant RAS/RAF are therapy refractory. Deregulated mRNA translation has become an emerging target in cancer treatment. We recently reported that mTOR inhibitors induce apoptosis via ER stress and the extrinsic pathway upon acute inhibition of the eIF4F complex in colon cancer cells and xenografts, while mutant BRAF600E leads to therapeutic resistance via ERK-mediated Mcl-1 stabilization. In this study, we demonstrated that several other translation inhibitors also activate ER stress and the extrinsic apoptotic pathway. Co-targeting translation and proteasome using the combination of Episilvestrol and Bortezomib promoted strong ER stress and rapid killing of colon cancer cells with mutant RAS/RAF in culture and mice. This combination led to marked induction of ER stress and ATF4/CHOP, followed by DR5- and BAX-dependent apoptosis, but unexpectedly with maintained or even increased levels of prosurvival factors such as p-AKT, p-4E-BP1, Mcl-1, and eiF4E targets c-Myc and Bcl-xL. Our study supports that targeting deregulated proteostasis is a promising approach for treating advanced colon cancer via induction of destructive ER stress that overcomes multiple resistance mechanisms associated with translation inhibition.