title: Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent downregulation of AKT and XIAP expressions.
abstract: 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.
authors: Mina and Everard Goodman Faculty of Life-Sciences, Bar-Ilan University, Ramat-Gan 52900 (CB), Israel.
authors: Sarit
authors: S
authors: Kahana
authors: Susan
authors: S
authors: Finniss
authors: Simona
authors: S
authors: Cazacu
authors: Cunli
authors: C
authors: Xiang
authors: Hae-Kyung
authors: HK
authors: Lee
authors: Shlomit
authors: S
authors: Brodie
authors: Ronald S
authors: RS
authors: Goldstein
authors: Vered
authors: V
authors: Roitman
authors: Shimon
authors: S
authors: Slavin
authors: Tom
authors: T
authors: Mikkelsen
authors: Chaya
authors: C
authors: Brodie
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005910:Glioma / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D007976:Leupeptins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde