Li Xiangyun, Li Mei, Ruan Hang, Qiu Wei, Xu Xiang, Zhang Lin, Yu Jian
First department, State Key Laboratory of Trauma, Burn and Combined Injury, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Daping, Yu Zhong District, Chongqing 400042, P.R. China.
Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Oncotarget. 2017 Feb 7;8(6):9280-9292. doi: 10.18632/oncotarget.14063.
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.
具有RAS/RAF突变的结直肠癌对治疗具有抗性。失调的mRNA翻译已成为癌症治疗中一个新出现的靶点。我们最近报道，在结肠癌细胞和异种移植瘤中急性抑制eIF4F复合物后，mTOR抑制剂通过内质网应激和外在途径诱导细胞凋亡，而突变型BRAF600E通过ERK介导的Mcl-1稳定导致治疗抗性。在本研究中，我们证明了其他几种翻译抑制剂也能激活内质网应激和外在凋亡途径。使用淫羊藿次苷和硼替佐米联合靶向翻译和蛋白酶体，在培养物和小鼠中能强烈激活内质网应激并快速杀死具有RAS/RAF突变的结肠癌细胞。这种联合导致内质网应激和ATF4/CHOP的显著诱导，随后是依赖DR5和BAX的细胞凋亡，但出乎意料的是，存活促进因子如p-AKT、p-4E-BP1、Mcl-1以及eIF4E靶标c-Myc和Bcl-xL的水平维持不变甚至升高。我们的研究支持，靶向失调的蛋白质稳态是一种有前景的治疗晚期结肠癌的方法，通过诱导破坏性的内质网应激来克服与翻译抑制相关的多种抗性机制。
