title: Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition.
abstract: Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to »100 μM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-κB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Young Dong
authors.initials: YD
authors.lastname: Yoo
authors.affiliation: Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Korea.|Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University Medical Center, Korea University, Seoul, Korea.
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience & Biotechnology, Ochang Cheongwon, Korea.
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Cha-Molstad
authors.affiliation: Department of Neurosurgery, College of Medicine Korea University Medical Center Korea University, Seoul, Korea.
authors.forename: Hyungsin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Su Ran
authors.initials: SR
authors.lastname: Mun
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Changhoon
authors.initials: C
authors.lastname: Ji
authors.affiliation: Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Korea.|Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University Medical Center, Korea University, Seoul, Korea.
authors.forename: Seong Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.|Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ki Sa
authors.initials: KS
authors.lastname: Sung
authors.affiliation: Division of Pediatric Neurosurgery, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Seung Ah
authors.initials: SA
authors.lastname: Choi
authors.affiliation: Department of Neurosurgery, College of Medicine Korea University Medical Center Korea University, Seoul, Korea.
authors.forename: Joonsung
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Deric M
authors.initials: DM
authors.lastname: Park
authors.affiliation: Division of Pediatric Neurosurgery, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, College of Medicine Korea University Medical Center Korea University, Seoul, Korea.
authors.forename: Kyung-Jae
authors.initials: KJ
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, College of Medicine Korea University Medical Center Korea University, Seoul, Korea.
authors.forename: Shin-Hyuk
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Korea.|Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University Medical Center, Korea University, Seoul, Korea.
authors.forename: Sang Cheul
authors.initials: SC
authors.lastname: Oh
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.|The Polak Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.affiliation: Departments of Surgery and Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA yok5@snu.ac.kr bykim@kribb.re.kr leeyj@upmc.edu.
authors.forename: Yong J
authors.identifier: 0000-0001-5914-8489
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, College of Medicine Korea University Medical Center Korea University, Seoul, Korea yok5@snu.ac.kr bykim@kribb.re.kr leeyj@upmc.edu.
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea yok5@snu.ac.kr bykim@kribb.re.kr leeyj@upmc.edu.|Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Yong Tae
authors.identifier: 0000-0002-8115-3150
authors.initials: YT
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex
keywords: apoptosis; c‐Jun N‐terminal kinase; glioma stem cells; proteasome inhibitors; ubiquitin proteasome system