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Title 

Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition

Authors 

Y D YooD H LeeHyunjoo ChaH KimS R MunC JiS H ParkK S SungS A ChoiJ HwangD M ParkS K KimK J ParkS H KangS C OhA CiechanoverY J LeeBo Yeon KimY T Kwon

Publisher 

EMBO Press

Issue Date 

2017

Citation 

EMBO Reports

Keywords 

apoptosis c-JunN-terminal kinaseglioma stem cellsproteasome inhibitorsubiquitin proteasome system

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

ISSN 

1469-222X

Link 

http://dx.doi.org/10.15252/embr.201642360

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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