Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent downregulation of AKT and XIAP expressions
| Autor: | Sarit Kahana, Tom Mikkelsen, Cunli Xiang, Simona Cazacu, Shlomit Brodie, Shimon Slavin, Vered Roitman, Susan Finniss, Hae Kyung Lee, Ronald S. Goldstein, Chaya Brodie |
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| Rok vydání: | 2011 |
| Předmět: |
Proteasome Endopeptidase Complex
Leupeptins Down-Regulation Apoptosis X-Linked Inhibitor of Apoptosis Protein Protein Kinase C-epsilon Bortezomib TNF-Related Apoptosis-Inducing Ligand Downregulation and upregulation Cell Line Tumor Glioma Antineoplastic Combined Chemotherapy Protocols medicine Humans Protease Inhibitors Protein kinase B Chemistry Cell Biology medicine.disease Boronic Acids Neural stem cell Cell biology XIAP Proteasome Astrocytes Pyrazines Mutagenesis Site-Directed Neoplastic Stem Cells Cancer research Stem cell Proteasome Inhibitors Proto-Oncogene Proteins c-akt |
| Zdroj: | Cellular Signalling. 23:1348-1357 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2011.03.017 |
| Popis: | In this study we examined the effects of proteasome inhibitors on cell apoptosis in TRAIL-resistant glioma cells and glioma stem cells (GSCs). Treatment with proteasome inhibitors and TRAIL induced apoptosis in all the resistant glioma cells and GSCs, but not in astrocytes and neural progenitor cells. Since PKCε has been implicated in the resistance of glioma cells to TRAIL, we examined its role in TRAIL and proteasome inhibitor-induced apoptosis. We found that TRAIL did not induce significant changes in the expression of PKCε, whereas a partial decrease in PKCε expression was obtained by proteasome inhibitors. A combined treatment of TRAIL and proteasome inhibitors induced accumulation of the catalytic fragment of PKCε and significantly and selectively decreased its protein and mRNA levels in the cancer but not in normal cells. Overexpression of PKCε partially inhibited the apoptotic effect of the proteasome inhibitors and TRAIL, and the caspase-resistant PKCεD383A mutant exerted a stronger inhibitory effect. Silencing of PKCε induced cell apoptosis in both glioma cells and GSCs, further supporting its role in cell survival. TRAIL and the proteasome inhibitors decreased the expression of AKT and XIAP in a PKCε-dependent manner and overexpression of these proteins abolished the apoptotic effect of this treatment. Moreover, silencing of XIAP sensitized glioma cells to TRAIL. Our results indicate that proteasome inhibitors sensitize glioma cells and GSCs to TRAIL by decreasing the expression of PKCε, AKT and XIAP. Combining proteasome inhibitors with TRAIL may be useful therapeutically in the treatment of gliomas and the eradication of GSCs. |
| Databáze: | OpenAIRE |
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