Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition
| Autor: | Joonsung Hwang, Sang Cheul Oh, Shin Hyuk Kang, Ki Sa Sung, Dae Hee Lee, Su Ran Mun, Hyungsin Kim, Young Dong Yoo, Changhoon Ji, Seong Hye Park, Kyung Jae Park, Deric M. Park, Yong J. Lee, Seung-Ki Kim, Kim Bo Yeon, Seung Ah Choi, Aaron Ciechanover, Yong Tae Kwon, Hyunjoo Cha-Molstad |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Apoptosis medicine.disease_cause Biochemistry Mice 0302 clinical medicine Tumor Cells Cultured Kinase NF-kappa B Glioma Articles Cell biology Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Neoplastic Stem Cells Stem cell Corrigendum Proteasome Inhibitors Signal Transduction Proteasome Endopeptidase Complex endocrine system Cell Survival Antineoplastic Agents Biology Models Biological 03 medical and health sciences Cancer stem cell Cell Line Tumor medicine Genetics Animals Humans Molecular Biology Endoplasmic reticulum fungi JNK Mitogen-Activated Protein Kinases Ubiquitination medicine.disease Xenograft Model Antitumor Assays Disease Models Animal 030104 developmental biology Proteasome Drug Resistance Neoplasm Cancer research Unfolded protein response Carcinogenesis Biomarkers 030215 immunology |
| Popis: | 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 (IC 50, 27–70 nM) compared with their differentiated controls (IC 50, 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. |
| Databáze: | OpenAIRE |
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