Daunorubicin-induced apoptosis: Triggering of ceramide generation through sphingomyelin hydrolysis
Daunorubicin-induced apoptosis: Triggering of ceramide generation through sphingomyelin hydrolysis
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DOI：
10.1002/j.1460-2075.1996.tb00599.x
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发表时间：
1996-05-15
期刊：
影响因子：
11.4
通讯作者：
Laurent, G
中科院分区：
文献类型：
--
作者：
Jaffrezou, JP;Levade, T;Laurent, G
引发药物触发细胞凋亡的信号通路的性质在很大程度上仍然未知，并且对于理解化疗药物诱导的细胞死亡具有根本重要性。在此，我们表明，在白血病细胞系 U937 和 HL-60 中，柔红霉素在触发细胞凋亡的浓度下，在 4-10 分钟内刺激了两个不同的鞘磷脂水解周期（类似于 1 μM 时减少 20%），并且60-75 分钟伴随神经酰胺生成，我们证明细胞凋亡之前的神经酰胺水平增加是由中性鞘磷脂酶介导的，而不是由神经酰胺合酶介导的。事实上，有效的神经酰胺合酶抑制剂如伏马菌素 B1 不会影响柔红霉素触发的鞘磷脂水解、神经酰胺生成或细胞凋亡。总之，我们提供证据表明柔红霉素触发的细胞凋亡是由信号通路介导的，该信号通路是由早期鞘磷脂衍生的神经酰胺产生启动的。
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.