Daunorubicin-induced apoptosis: Triggering of ceramide generation through sphingomyelin hydrolysis

被引:346
作者
Jaffrezou, JP
Levade, T
Bettaieb, A
Andrieu, N
Bezombes, C
Maestre, N
Vermeersch, S
Rousse, A
Laurent, G
机构
[1] CHU RANGUEIL,INSERM,CJF 9206,LAB BIOCHIM MED,F-31054 TOULOUSE,FRANCE
[2] CHU PURPAN,SERV HEMATOL,F-31059 TOULOUSE,FRANCE
关键词
ceramide; daunorubicin; sphingolipid signaling pathway; sphingomyelin;
D O I
10.1002/j.1460-2075.1996.tb00599.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The nature of the signaling pathway(s) which initiate drug-triggered apoptosis remains largely unknown and is of fundamental importance in understanding cell death induced by chemotherapeutic agents, Here we show that in the leukemic cell lines U937 and HL-60, daunorubicin, at concentrations which trigger apoptosis, stimulated two distinct cycles of sphingomyelin hydrolysis (similar to 20% decrease at 1 mu M) within 4-10 min and 60-75 min with concomitant ceramide generation, We demonstrate that the increase in ceramide levels, which precedes apoptosis, is mediated by a neutral sphingomyelinase and not by ceramide synthase, Indeed, potent ceramide synthase inhibitors such as fumonisin B1 did not affect daunorubicin-triggered sphingomyelin hydrolysis, ceramide generation or apoptosis, In conclusion, we provide evidence that daunorubicin-triggered apoptosis is mediated by a signaling pathway which is initiated by an early sphingomyelin-derived ceramide production.
引用
收藏
页码:2417 / 2424
页数:8
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