Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells
Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells
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DOI：
10.1038/sj.onc.1210672
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发表时间：
2008-01-31
期刊：
影响因子：
8
通讯作者：
Kamijo, T.
中科院分区：
文献类型：
--
作者：
Kurata, K.;Yanagisawa, R.;Kamijo, T.
在这项研究中，我们采用了一个面板的细胞系，以确定是否p53依赖性细胞死亡的神经母细胞瘤（NB）细胞是由细胞凋亡的功能，我们进一步研究了通过p53依赖性途径诱导细胞凋亡的分子机制。我们获得的证据表明，一种类型的p53依赖性应激，阿霉素（Doxo）管理，导致积累的p53在NB细胞的细胞核和磷酸化的几个丝氨酸残基在Doxo敏感和耐药细胞系。仅在Doxo敏感的NB细胞中观察到细胞中p53下游分子的上调和线粒体组分中Noxa的上调。通过Noxa敲低实验证实了Noxa在Doxo诱导的NB细胞死亡中的意义。线粒体功能障碍，包括细胞色素C释放和膜电位失调，发生并导致内在caspase途径的激活。然而，在Doxo抗性细胞中，p53在细胞核中的积累和磷酸化并不诱导p53下游p21（Cip 1/Waf 1）表达和Noxa上调，从而导致线粒体稳态的保持。总而言之，这些发现表明p53途径似乎通过线粒体中的Noxa调节在NB细胞死亡中发挥关键作用，并且抑制p53下游效应物的诱导可能会调节NB细胞的耐药性。
In this study, we employed a panel of cell lines to determine whether p53-dependent cell death in neuroblastoma (NB) cells is caused by apoptotic cellular function, and we further studied the molecular mechanism of apoptosis induced via the p53-dependent pathway. We obtained evidence that a type of p53-dependent stress, doxorubicin (Doxo) administration, causes accumulation of p53 in the nucleus of NB cells and phosphorylation of several serine residues in both Doxo-sensitive and -resistant cell lines. Upregulation of p53-downstream molecules in cells and upregulation of Noxa in the mitochondrial fraction were observed only in Doxo-sensitive NB cells. Significance of Noxa in the Doxo-induced NB cell death was confirmed by Noxa-knockdown experiments. Mitochondrial dysfunction, including cytochrome-c release and membrane potential disregulation, occurred and resulted in the activation of the intrinsic caspase pathway. However, in the Doxo-resistant cells, the accumulation in the nucleus and phosphorylation of p53 did not induce p53-downstream p21(Cip1/Waf1) expression and the Noxa upregulation, resulting in the retention of the mitochondrial homeostasis. Taken together, these findings indicate that the p53 pathway seems to play a crucial role in NB cell death by Noxa regulation in mitochondria, and inhibition of the induction of p53-downstream effectors may regulate drug resistance of NB cells.