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.
| Original language | English |
|---|---|
| Pages (from-to) | 150-168 |
| Number of pages | 19 |
| Journal | EMBO Reports |
| Volume | 18 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2017 Jan 1 |
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Keywords
- apoptosis
- c-Jun N-terminal kinase
- glioma stem cells
- proteasome inhibitors
- ubiquitin proteasome system
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Genetics
Cite this
Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition. / Yoo, Young Dong; Lee, Dae Hee; Cha-Molstad, Hyunjoo; Kim, Hyungsin; Mun, Su Ran; Ji, Changhoon; Park, Seong Hye; Sung, Ki Sa; Choi, Seung Ah; Hwang, Joonsung; Park, Deric M.; Kim, Seung Ki; Park, Kyung-Jae; Kang, Shin-Hyuk; Oh, Sang Cheul; Ciechanover, Aaron; Lee, Yong J.; Kim, Bo Yeon; Kwon, Yong Tae.
In: EMBO Reports, Vol. 18, No. 1, 01.01.2017, p. 150-168.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition
AU - Yoo, Young Dong
AU - Lee, Dae Hee
AU - Cha-Molstad, Hyunjoo
AU - Kim, Hyungsin
AU - Mun, Su Ran
AU - Ji, Changhoon
AU - Park, Seong Hye
AU - Sung, Ki Sa
AU - Choi, Seung Ah
AU - Hwang, Joonsung
AU - Park, Deric M.
AU - Kim, Seung Ki
AU - Park, Kyung-Jae
AU - Kang, Shin-Hyuk
AU - Oh, Sang Cheul
AU - Ciechanover, Aaron
AU - Lee, Yong J.
AU - Kim, Bo Yeon
AU - Kwon, Yong Tae
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - apoptosis
KW - c-Jun N-terminal kinase
KW - glioma stem cells
KW - proteasome inhibitors
KW - ubiquitin proteasome system
UR - http://www.scopus.com/inward/record.url?scp=85006983243&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006983243&partnerID=8YFLogxK
U2 - 10.15252/embr.201642360
DO - 10.15252/embr.201642360
M3 - Article
C2 - 27993939
AN - SCOPUS:85006983243
VL - 18
SP - 150
EP - 168
JO - EMBO Reports
JF - EMBO Reports
SN - 1469-221X
IS - 1
ER -