Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKC epsilon-dependent downregulation of AKT and XIAP expressions

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 PKC epsilon 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 PKC epsilon, whereas a partial decrease in PKC epsilon expression was obtained by proteasome inhibitors. A combined treatment of TRAIL and proteasome inhibitors induced accumulation of the catalytic fragment of PKC epsilon and significantly and selectively decreased its protein and mRNA levels in the cancer but not in normal cells. Overexpression of PKC epsilon partially inhibited the apoptotic effect of the proteasome inhibitors and TRAIL and the caspase-resistant PKC epsilon D383A mutant exerted a stronger inhibitory effect. Silencing of PKC epsilon 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 PKC epsilon-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 PKC epsilon, AKT and XIAP. Combining proteasome inhibitors with TRAIL may be useful therapeutically in the treatment of gliomas and the eradication of GSCs. (C) 2011 Elsevier Inc. All rights reserved.