@article{ec7c8233322b4a2b8ab76a699ac941f2,
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.",
keywords = "apoptosis, c-Jun N-terminal kinase, glioma stem cells, proteasome inhibitors, ubiquitin proteasome system",
author = "Yoo, {Young Dong} and Lee, {Dae Hee} and Hyunjoo Cha-Molstad and Hyungsin Kim and Mun, {Su Ran} and Changhoon Ji and Park, {Seong Hye} and Sung, {Ki Sa} and Choi, {Seung Ah} and Joonsung Hwang and Park, {Deric M.} and Kim, {Seung Ki} and Park, {Kyung Jae} and Kang, {Shin Hyuk} and Oh, {Sang Cheul} and Aaron Ciechanover and Lee, {Yong J.} and Kim, {Bo Yeon} and Kwon, {Yong Tae}",
note = "Funding Information: We thank Drs. Daniel Finley, Jon Clardy (Harvard University), and Jae J. Song (Yonsei University) for providing us with PS341, salinosporamide A, and TRAIL, respectively; Kyoung Tae Seo (Soongsil University) and Su Jin Yoo (University of Wisconsin-Madison) for technical assistance; and Edward Kwak (Viagen Biotech Inc., USA) for editorial assistance. This work was supported by the SNU Nobel Laureates Invitation Program (to A.C.), the Basic Science Research Programs of the NRF funded by the Ministry of Science, ICT and Future Planning (MSIP) (NRF-2016R1A2B3011389 to Y.T.K. and 2015R1D1A1A01058303 to D.H.L.) and the Ministry of Education (NRF-2013R1A1A2058983 to Y.D.Y), Seoul National University Hospital (to Y.T.K.), the National Cancer Institute grant CA140554 (to Y.J.L), the World Class Institute (WCI) Program of the NRF funded by the MSIP (WCI 2009-002 to B.Y.K.), the R&D Convergence Program (CAP-16-03-KRIBB to B.Y.K.) of NST of Korea, the Bio and Medical Technology Development Program (NRF-2014M39Ab5073938 to B.Y.K.) of MSIP and KRIBB Research Initiative Program, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF) (to A.C.), and the Israel Science Foundation (ISF) (to A.C.). A.C. is an Israel Cancer Research Fund (ICRF), USA Professor.",
year = "2017",
month = jan,
day = "1",
doi = "10.15252/embr.201642360",
language = "English",
volume = "18",
pages = "150--168",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "1",
}