文章：

PKR负调控白血病进展，与PP2A激活、Bcl-2抑制和细胞凋亡增加有关

PKR negatively regulates leukemia progression in association with PP2A activation, Bcl-2 inhibition and increased apoptosis

原文发布日期：2013-09-06

DOI: 10.1038/bcj.2013.42

类型: Original Article

开放获取: 是

英文摘要：

Reduced expression and activity of the proapoptotic, double-stranded RNA-dependent protein kinase, PKR (protein kinase R) is observed in breast, lung and various leukemias, suggesting that loss of PKR potentiates transformation. Now we report that decreased PKR activity inhibits chemotherapy-induced apoptosis of leukemia cells both in vitro and in vivo. Inhibition of PKR expression or activity reduces protein phosphatase 2A (PP2A) activity, a B-cell lymphoma 2 (Bcl-2) phosphatase, resulting in enhanced Bcl-2 phosphorylation. Thus, inhibition of PKR activity leads to hyperphosphorylation of Bcl-2, stabilization of Bcl-2/Bax interaction and decreased Bax insertion into the outer mitochondrial membrane. Treatment with the PP2A activator, FTY720, restores Bcl-2 dephosphorylation and apoptosis in cells with reduced PKR expression following stress. Significantly, xenografts of REH leukemic cells with reduced PKR display significantly increased tumor volume, increased resistance to doxorubicin treatment and shorter survival. Importantly, FTY720 treatment restores sensitivity to chemotherapy and prolongs overall survival of these mice. Collectively, these findings suggest that PP2A activation is a downstream target of PKR and the PKR/PP2A signaling axis is required for rapid and potent stress-induced apoptosis. Importantly, loss of PKR promotes leukemia progression and may serve as a biomarker for predicting chemosensitivity.

摘要翻译： 

在乳腺癌、肺癌和各种白血病中观察到促凋亡双链RNA依赖性蛋白激酶PKR的表达和活性降低，这表明PKR的缺失会促进细胞转化。现在我们发现，PKR活性降低会抑制白血病细胞在体外和体内化疗诱导的凋亡。抑制PKR表达或活性会降低蛋白磷酸酶2A（PP2A）的活性（一种B细胞淋巴瘤2（Bcl-2）磷酸酶），从而导致Bcl-2磷酸化增强。因此，抑制PKR活性会导致Bcl-2过度磷酸化、Bcl-2/Bax相互作用稳定化以及Bax插入线粒体外膜减少。使用PP2A激活剂FTY720处理，可在应激后恢复PKR表达降低的细胞中Bcl-2的去磷酸化和凋亡。值得注意的是，PKR降低的REH白血病细胞异种移植瘤显示肿瘤体积显著增加、对阿霉素治疗的耐药性增加以及存活期缩短。重要的是，FTY720治疗可恢复对这些小鼠的化疗敏感性并延长总生存期。总的来说，这些发现表明PP2A激活是PKR的下游靶点，并且PKR/PP2A信号轴是快速有效的应激诱导凋亡所必需的。重要的是，PKR的缺失会促进白血病进展，并可能作为预测化疗敏感性的生物标志物。

原文链接：

PKR negatively regulates leukemia progression in association with PP2A activation, Bcl-2 inhibition and increased apoptosis