p53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent pathway in SH-SY5Y neuroblastoma cells.
p53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent pathway in SH-SY5Y neuroblastoma cells.
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发表时间：
2002-07
影响因子：
5.7
通讯作者：
H. Cui;A. Schroering;H. Ding
中科院分区：
文献类型：
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作者：
H. Cui;A. Schroering;H. Ding
在化学敏感的人神经母细胞瘤细胞系SH-SY 5 Y中检查DNA损伤药物触发的细胞凋亡的信号通路。多柔比星和足叶乙甙诱导SH-SY 5 Y细胞快速广泛凋亡。药物治疗后，细胞核中p53蛋白水平增加，导致其转录靶点p21（Waf 1/Cip 1）和MDM 2的诱导。通过人乳头瘤病毒16型E6蛋白或显性阴性突变型p53（R175 H）灭活p53，完全保护SH-SY 5 Y细胞免于药物触发的凋亡。细胞色素c和caspase-9在p53下游介导药物引发的SH-SY 5 Y细胞凋亡中发挥作用。在药物处理的细胞中，细胞色素c被释放，caspase-9被激活。p53的失活阻断了细胞色素c的释放和半胱天冬酶-9的激活。此外，药物诱导的细胞死亡可以通过表达胱天蛋白酶-9的显性负突变体来预防。这些研究结果定义了一个分子途径介导的DNA损伤药物诱导的人神经母细胞瘤SH-SY 5 Y细胞凋亡，并表明，失活的必要组成部分，这种凋亡途径可能会赋予神经母细胞瘤细胞的耐药性。
The signaling pathway for DNA damaging drug-triggered apoptosis was examined in a chemosensitive human neuroblastoma cell line, SH-SY5Y. Doxorubicin and etoposide induce rapid and extensive apoptosis in SH-SY5Y cells. After the drug treatment, p53 protein levels increase in the nucleus, leading to the induction of its transcription targets p21(Waf1/Cip1) and MDM2. Inactivation of p53, either by the human papillomavirus type 16 E6 protein or by a dominant-negative mutant p53 (R175H), completely protects SH-SY5Y cells from drug-triggered apoptosis. Cytochrome c and caspase-9 function downstream of p53 in mediating the drug-triggered apoptosis in SH-SY5Y cells. In drug-treated cells, cytochrome c is released, and caspase-9 becomes activated. Inactivation of p53 blocks cytochrome c release and caspase-9 activation. Furthermore, drug-induced cell death can be prevented by expression of a dominant-negative mutant of caspase-9. These findings define a molecular pathway for mediating DNA damaging drug-induced apoptosis in the human neuroblastoma SH-SY5Y cells and suggest that inactivation of essential components of this apoptotic pathway may confer drug resistance on neuroblastoma cells.