Bcl-2 overexpression prevents daunorubicin-induced apoptosis through inhibition of XIAP and Akt degradation

Abstract

Daunorubicin (DNR) induces apoptosis in the human myeloid leukemia cells by activation of neutral sphingomyelin ease and ceramide production. In the present study, we determined the effect of the antiapoptosis protein Bcl-2 on caspase-3 activation, phospholipase C-gamma1 (PLC-gamma1) degradation and cytochrome c release during the DNR-induced apoptosis. Treatment with 3 muM DNR for 12 hr produced morphological features of apoptosis and DNA fragmentation in U937 cells, which was associated with caspase-3 activation and PLC-gamma1 degradation. Induction of apoptosis was also accompanied by release of cytochrome c, down-regulation of X-linked inhibitor of apoptosis protein (XIAP), and inactivation of Akt, which was blocked by the pan-caspase inhibitor z-VAD-fmk. DNR-induced caspase-3 activation, PLC-gamma1 degradation and apoptosis were significantly attenuated in Bcl-2 overexpressing U937/Bcl-2 cells. Ectopic expression of Bcl-2 appeared to inhibit DNR-induced apoptosis by interfering with inhibition of XIAP and Akt degradation. (C) 2003 Elsevier Inc. All rights reserved.