Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells.
Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells.
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DOI：
10.1074/jbc.m109.014092
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发表时间：
2010-02-26
期刊：
影响因子：
--
通讯作者：
Redfern CP
中科院分区：
文献类型：
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作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
神经外胚层肿瘤、神经母细胞瘤和黑色素瘤代表了具有生物侵袭性和耐药性的癌症。我们以前已经证明，化疗药物芬维A胺和硼替佐米诱导细胞凋亡，通过内质网（ER）的压力，在这些肿瘤类型。本研究的目的是验证以下假设：芬维A胺和硼替佐米诱导的ER应激信号传导和反应途径的早期事件是由eIF 2 α-ATF 4信号传导途径介导的。用芬维A胺、硼替佐米或毒胡萝卜素处理神经母细胞瘤和黑色素瘤细胞系导致eIF 2 α信号传导的诱导，其特征在于磷酸化eIF 2 α、ATF 4、ATF 3和GADD 34的表达增加。这些事件与促凋亡蛋白Noxa的诱导相关。细胞毒性反应的特征是Noxa和细胞死亡的上调，依赖于ATF 4，但不依赖于涉及GADD 153或IRE 1的ER相关促死亡信号通路。虽然ERK依赖的eIF 2 α磷酸化在ER应激期间增强了ATF 4蛋白水平，但通过ERK敲低或野生型eIF 2 α过表达抑制eIF 2 α磷酸化并不能消除响应于芬维A胺、硼替佐米或毒胡萝卜素的细胞死亡。此外，响应ER应激的ATF 4诱导主要依赖于转录激活，其以PERK和磷酸化eIF 2 α非依赖性方式发生。这些结果表明，ATF 4介导的神经外胚层肿瘤细胞响应于芬维A胺或硼替佐米的ER应激诱导的细胞死亡。了解ER应激诱导药物对细胞死亡途径的复杂调控有可能揭示新的治疗靶点，从而允许开发改进的治疗策略以克服化疗耐药性。
The neuroectodermal tumours neuroblastoma and melanoma represent biologically aggressive and chemoresistant cancers. We have previously demonstrated that the chemotherapeutic agents fenretinide and bortezomib induce apoptosis through endoplasmic reticulum (ER) stress in these tumour types. The aim of this study was to test the hypothesis that the early events of ER stress signalling and response pathways induced by fenretinide and bortezomib are mediated by the eIF2α-ATF4 signalling pathway. Treatment of neuroblastoma and melanoma cell lines with fenretinide, bortezomib or thapsigargin resulted in induction of eIF2α signalling, characterised by increased expression of phosphorylated eIF2α, ATF4, ATF3 and GADD34. These events correlated with induction of the pro-apoptotic protein Noxa. The cytotoxic response, characterised by the up-regulation of Noxa and cell death, was dependent on ATF4, but not the ER-related pro-death signalling pathways involving GADD153 or IRE1. While PERK-dependent phosphorylation of eIF2α enhanced ATF4 protein levels during ER stress, cell death in response to fenretinide, bortezomib or thapsigargin was not abrogated by inhibition of eIF2α phosphorylation through PERK knockdown or overexpression of wild-type eIF2α. Furthermore, ATF4 induction in response to ER stress was primarily dependent on transcriptional activation, which occurred in a PERK- and phosphorylated eIF2α-independent manner. These results demonstrate that ATF4 mediates ER stress-induced cell death of neuroectodermal tumour cells in response to fenretinide or bortezomib. Understanding the complex regulation of cell death pathways in response to ER stress-inducing drugs has the potential to reveal novel therapeutic targets, thus allowing the development of improved treatment strategies to overcome chemoresistance.