title: Co-targeting translation and proteasome rapidly kills colon cancer cells with mutant RAS/RAF via ER stress.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xiangyun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Animal Genetics, Breeding and Reproduction, Nanjing Agricultural University, Weigang, Nanjing 210095, P.R. China.|Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Ruan
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.affiliation: 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.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008819:Mice, Nude; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C117307:KRAS protein, human; D061988:Proteasome Inhibitors; D011500:Protein Synthesis Inhibitors; D014315:Triterpenes; C489893:episilvestrol; D000069286:Bortezomib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D046988:Proteasome Endopeptidase Complex; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Bax; CHOP; DR5; ER stress; translation