The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction.
The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction.
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DOI：
10.1038/bjc.2012.139
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发表时间：
2012-05-08
影响因子：
8.8
通讯作者：
Amiot, M.
中科院分区：
文献类型：
--
作者：
Descamps, G.;Gomez-Bougie, P.;Tamburini, J.;Green, A.;Bouscary, D.;Maiga, S.;Moreau, P.;Le Gouill, S.;Pellat-Deceunynck, C.;Amiot, M.
癌细胞经常依赖于失调的致癌蛋白质翻译。小分子4 EG-I选择性地抑制mRNA的帽依赖性翻译。由于多发性骨髓瘤是一种无法治愈的疾病，需要新的治疗方法，我们研究了靶向翻译起始途径是否可以成为骨髓瘤治疗的靶点。本研究包括六种骨髓瘤细胞系和原代样本。通过AnnexinV染色和半胱天冬酶活化来确定4 EGI-1的作用。分析Bcl-2蛋白表达的修饰，并通过敲低实验分析修饰蛋白的意义。我们证明，4 EGI-1损害了eIF 4F复合物的组装，并降低了骨髓瘤细胞中eIF 4 E调节蛋白的表达。此外，我们发现4 EGI-1在六个骨髓瘤细胞系中的五个中诱导强烈的凋亡。细胞凋亡与内在线粒体途径的激活有关。4 EGI-1仅在通过内质网（ER）应激经历凋亡的细胞中触发Noxa诱导。此外，Noxa沉默阻止骨髓瘤细胞4 EGI-1诱导的凋亡。最后，Noxa诱导导致Mcl-1/Bim复合物的破坏，同时产生“无Mcl-1 Noxa”。我们的研究结果表明，使用直接靶向翻译起始复合物eIF 4F的抑制剂可能是多发性骨髓瘤治疗的一种潜在的新方法。
Cancer cells are frequently addicted to deregulated oncogenic protein translation. The small molecule 4EG-I selectively inhibits the cap-dependent translation of mRNAs. As multiple myeloma is an incurable disease that requires new therapeutic approaches, we investigated whether targeting the translation initiation pathway could be a target for myeloma therapy. Six myeloma cell lines and primary samples were included in this study. The 4EGI-1 effect was determined by AnnexinV staining and caspase activation. Modification of Bcl-2 protein expression was analysed, and the significance of modified proteins was analysed by knock-down experiments. We demonstrated that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E-regulated proteins in myeloma cells. Furthermore, we showed that 4EGI-1 induced strong apoptosis in five out of six myeloma cell lines. Apoptosis is associated with the activation of the intrinsic mitochondrial pathway. The 4EGI-1 triggered Noxa induction only in cells undergoing apoptosis through endoplasmic reticulum (ER) stress. Furthermore, Noxa silencing prevented myeloma cells from 4EGI-1-induced apoptosis. Finally, Noxa induction led to a disruption of Mcl-1/Bim complexes in parallel to the generation of ‘Mcl-1-free Noxa’. Our results suggested that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for multiple myeloma therapy.
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DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
5.4
作者：
Gomez-Bougie, P;Bataille, R;Amiot, M
通讯作者：
Amiot, M
影响因子：
4.3
作者：
Konicek, Bruce W.;Dumstorf, Chad A.;Graff, Jeremy R.
通讯作者：
Graff, Jeremy R.
影响因子：
82.9
作者：
Ruggero, D;Montanaro, L;Pandolfi, PP
通讯作者：
Pandolfi, PP