Co-targeting translation and proteasome rapidly kills colon cancer cells with mutant RAS/RAF via ER stress
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Xiangyun Li1,3,*, Mei Li2,3,*, Hang Ruan3, Wei Qiu1, Xiang Xu1, Lin Zhang4, Jian Yu3
1First 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
2Department of Animal Genetics, Breeding and Reproduction, Nanjing Agricultural University, Weigang, Nanjing 210095, P.R. China
3Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
4Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
*These authors contributed equally to this work
Mei Li, email: email@example.com
Jian Yu, email: firstname.lastname@example.org
Xiang Xu, email: email@example.com
Keywords: translation, ER stress, CHOP, DR5, Bax
Received: October 26, 2016 Accepted: December 13, 2016 Published: January 22, 2018
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.
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