Bcl-2 overexpression prevents daunorubicin-induced apoptosis through inhibition of XIAP and Akt degradation.
Daunorubicin (DNR) induces apoptosis in the human myeloid leukemia cells by activation of neutral sphingomyelinease and ceramide production. In the present study, we determined the effect of the antiapoptosis protein Bcl-2 on caspase-3 activation, phospholipase C-gamma 1 (PLC-gamma 1) degradation and cytochrome c release during the DNR-induced apoptosis. Treatment with 3 microM DNR for 12 hr produced morphological features of apoptosis and DNA fragmentation in U937 cells, which was associated with caspase-3 activation and PLC-gamma 1 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-gamma 1 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.
Kim
Young-Ho
YH
Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
Park
Jong-Wook
JW
Lee
Jai-Youl
JY
Surh
Young-Joon
YJ
Kwon
Taeg Kyu
TK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003630:Daunorubicin / Q000494:pharmacology*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C030193:immunosuppressive acidic protein; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003630:Daunorubicin