Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells
Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells
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DOI：
10.1038/sj.onc.1205879
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发表时间：
2002-09-05
期刊：
影响因子：
8
通讯作者：
Gross, N
中科院分区：
文献类型：
--
作者：
Hopkins-Donaldson, S;Yan, P;Gross, N
神经母细胞瘤 (NB) 细胞中阿霉素 (dox) 诱导的死亡最初被认为是通过 Fas 途径发生的，然而，由于研究表明 caspase-8 表达在大多数晚期 NB 肿瘤中被沉默，因此 dox 诱导的死亡更有可能是通过不同的机制发生的。研究了 Caspase-8 沉默的 N 型侵袭性 NB 细胞 LAN-1 和 IMR-32 对 dox 的敏感性，并与表达 caspase-8 的 S 型非侵袭性 SH-EP NB 细胞进行比较。所有细胞系对 dox 都有相似的敏感性，与 caspase-8 表达无关。 Dox 诱导 S 型细胞中的 caspase-3、-7、-8 和 -9 和 Bid 裂解和死亡被 caspase 抑制剂阻断，但不能被氧自由基清除剂 BHA 阻断。相比之下，dox 诱导的 N 型细胞死亡不依赖于 caspase，并被 BHA 抑制。 Dox 诱导所有细胞系线粒体膜通透性下降。在S型细胞中，Dox诱导的死亡产生凋亡细胞核，而在N型细胞中，细胞核在形态上是非凋亡的。用显性失活 FADD 突变体转染 SH-EP 细胞可抑制 TRAIL 诱导的死亡，但对 dox 诱导的细胞凋亡没有影响。这些结果表明，S 型细胞在 dox 处理后独立于死亡受体发生凋亡，而 N 型细胞则通过不依赖于 caspase 的机制被杀死。
Death induced by doxorubicin (dox) in neuroblastoma (NB) cells was originally thought to occur via the Fas pathway, however since studies suggest that caspase-8 expression is silenced in most high stage NB tumors, it is more probable that dox-induced death occurs via a different mechanism. Caspase-8 silenced N-type invasive NB cell tines LAN-1 and IMR-32 were investigated for their sensitivity to dox, and compared to S-type noninvasive SH-EP NB cells expressing caspase-8. All cell lines had similar sensitivities to dox, independently of caspase-8 expression. Dox induced caspase-3, -7, -8 and -9 and Bid cleavage in S-type cells and death was blocked by caspase inhibitors but not by oxygen radical scavenger BHA. In contrast, dox-induced death in N-type cells was caspase-independent and was inhibited by BHA. Dox induced a drop in mitochondrial membrane permeability in all cell lines. Dox-induced death in S-type cells gave rise to apoptotic nuclei, whereas in N-type cells nuclei were non-apoptotic in morphology. Transfection of SH-EP cells with a dominant negative FADD mutant inhibited TRAIL-induced death, but had no effect on dox-induced apoptosis. These results suggest that S-type cells undergo apoptosis after dox treatment independently of death receptors, whereas N-type cells are killed by a caspase-independent mechanism.