PKR negatively regulates leukemia progression in association with PP2A activation, Bcl-2 inhibition and increased apoptosis.
PKR negatively regulates leukemia progression in association with PP2A activation, Bcl-2 inhibition and increased apoptosis.
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DOI：
10.1038/bcj.2013.42
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发表时间：
2013-09-06
影响因子：
12.8
通讯作者：
May, W. Stratford
中科院分区：
文献类型：
--
作者：
Cheng, X.;Bennett, R. L.;Liu, X.;Byrne, M.;May, W. Stratford
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（蛋白激酶R）的表达和活性降低，表明PKR的丧失增强了转化。现在，我们报告PKR活性降低抑制化疗诱导的白血病细胞凋亡在体外和体内。PKR表达或活性的抑制降低了蛋白磷酸酶2A（PP 2A）活性，这是一种B细胞淋巴瘤2（Bcl-2）磷酸酶，导致Bcl-2磷酸化增强。因此，PKR活性的抑制导致Bcl-2的过度磷酸化、Bcl-2/Bax相互作用的稳定化和Bax插入线粒体外膜的减少。用PP 2A激活剂FTY 720处理恢复了应激后PKR表达降低的细胞中Bcl-2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物显示出显著增加的肿瘤体积，增加的对阿霉素治疗的抗性和较短的生存期。重要的是，FTY 720治疗恢复了对化疗的敏感性，并提高了这些小鼠的总体生存率。总的来说，这些发现表明，PP 2A活化是PKR的下游靶点，PKR/PP 2A信号传导轴是快速和有效的应激诱导的细胞凋亡所必需的。重要的是，PKR的缺失促进白血病进展，并可作为预测化疗敏感性的生物标志物。
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.
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影响因子：
3.7
作者：
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