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EMBO Rep. 2017 Jan;18(1):150-168. doi: 10.15252/embr.201642360. Epub 2016 Dec 19.

Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition.

Author information

1
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
2
Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.
3
Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul, Korea.
4
Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University Medical Center, Korea University, Seoul, Korea.
5
World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience & Biotechnology, Ochang Cheongwon, Korea.
6
Department of Neurosurgery, College of Medicine Korea University Medical Center Korea University, Seoul, Korea.
7
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
8
Division of Pediatric Neurosurgery, College of Medicine, Seoul National University, Seoul, Korea.
9
Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA, USA.
10
The Polak Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
11
Departments of Surgery and Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA yok5@snu.ac.kr bykim@kribb.re.kr leeyj@upmc.edu.
12
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.
13
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.
14
Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Korea.

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.

KEYWORDS:

apoptosis; c‐Jun N‐terminal kinase; glioma stem cells; proteasome inhibitors; ubiquitin proteasome system

PMID:
27993939
PMCID:
PMC5210095
DOI:
10.15252/embr.201642360
[Indexed for MEDLINE]
Free PMC Article

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