Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells
Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells
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DOI：
10.1038/sj.cdd.4400793
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发表时间：
2001-02-01
影响因子：
12.4
通讯作者：
Spiegel, S
中科院分区：
文献类型：
--
作者：
Cuvillier, O;Nava, VE;Spiegel, S
多柔比星是临床肿瘤学中使用的最活跃的促凋亡剂之一，用多柔比星处理人乳腺癌MCF 7细胞可诱导细胞凋亡并导致鞘氨醇水平增加。这种鞘脂介体的瞬时产生先于细胞色素c从线粒体释放和不表达半胱天冬酶-3的MCF 7细胞中的刽子手半胱天冬酶-7的激活。Bcl-x（L）过表达不影响鞘氨醇的生成，但可减少阿霉素诱导的细胞凋亡，并完全阻断鞘氨醇诱导的细胞凋亡。外源性鞘氨醇诱导的细胞凋亡还伴随细胞色素c的释放和caspase-7的激活，这是Bcl-x（L）敏感的方式。此外，阿霉素和鞘氨醇治疗均不影响Fas配体的表达或诱导顶端caspase-8的活化，表明Fas/Fas配体非依赖性机制。我们的研究结果表明，神经酰胺，鞘氨醇的进一步代谢产物，也可能参与在人乳腺癌细胞中阿霉素诱导的神经胶质瘤介导的凋亡信号。
Treatment of human breast carcinoma MCF7 cells with doxorubicin, one of the most active antineoplastic agents used in clinical oncology, induces apoptosis and leads to increases in sphingosine levels. The transient generation of this sphingolipid mediator preceded cytochrome c release from the mitochondria and activation of the executioner caspase-7 in MCF7 cells which do not express caspase-3. Bcl-x(L) overexpression did not affect sphingosine generation whereas it reduced apoptosis triggered by doxorubicin and completely blocked apoptosis triggered by sphingosine, Exogenous sphingosine-induced apoptosis was also accompanied by cytochrome c release and activation of caspase-7 in a Bcl-x(L)-sensitive manner. Furthermore, neither doxorubicin nor sphingosine treatment affected expression of Fas ligand or induced activation of the apical caspase-8, indicating a Fas/Fas ligand-independent mechanism. Our results suggest that a further metabolite of ceramide, sphingosine, may also be involved in mitochondria-mediated apoptotic signaling induced by doxorubicin in human breast cancer cells.