RNA-dependent protein kinase (PKR) depletes nutrients, inducing phosphorylation of AMP-activated kinase in lung cancer.
RNA-dependent protein kinase (PKR) depletes nutrients, inducing phosphorylation of AMP-activated kinase in lung cancer.
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DOI：
10.18632/oncotarget.3573
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发表时间：
2015-05-10
期刊：
影响因子：
--
通讯作者：
Pataer A
中科院分区：
文献类型：
--
作者：
Guo C;Hao C;Shao R;Fang B;Correa AM;Hofstetter WL;Roth JA;Behrens C;Kalhor N;Wistuba II;Swisher SG;Pataer A
我们已经证明 RNA 依赖性蛋白激酶 (PKR) 及其下游蛋白 p-eIF2α 是肺癌总体生存的独立预后标志物。在本研究中，我们进一步研究肺肿瘤组织和癌细胞系中PKR和AMPK之间的相互作用。我们通过蛋白质印迹法检查了 55 个冰冻原发性肺肿瘤组织中的 PKR 蛋白表达，并分析了 PKR 表达与先前通过反相蛋白阵列 (RPPA) 检查的来自同一 55 名患者的组织样本中 139 个蛋白表达子之间的关联。我们观察到生物标志物与 PKR 呈正相关（磷酸化 AMP 激活激酶 T172 [p-AMPK]）或负相关（胰岛素受体底物 1、减数分裂重组 11、ATR 相互作用蛋白、端粒酶、检查点激酶 1 和细胞周期蛋白 E1）。我们进一步证实，在肺癌细胞中用表达载体诱导 PKR 会导致 AMPK 蛋白的激活，而与 LKB1、TAK1 和 CaMKKβ 途径无关。我们发现 PKR 会导致营养消耗，从而增加 AMP 水平并降低 ATP 水平，从而导致 AMPK 磷酸化。我们进一步证明，用化合物 C 或 siRNA 抑制 AMPK 表达可增强 PKR 介导的细胞死亡。接下来，我们探讨了 NSCLC 患者中 PKR 和 p-AMPK 表达的组合，并观察到 p-AMPK 的表达预示着 PKR 高表达的腺癌患者预后较差，而 PKR 表达低的腺癌患者预后较好。这些发现与我们的体外结果一致。 AMPK 可能会拯救面临代谢应激（例如 PKR 引起的 ATP 耗竭）的细胞。我们的数据表明 PKR 会导致营养消耗，从而诱导 AMPK 磷酸化。 AMPK 可能对代谢应激（例如营养缺乏）起到保护性反应。
We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2α are independent prognostic markers for overall survival in lung cancer. In the current study, we further investigate the interaction between PKR and AMPK in lung tumor tissue and cancer cell lines. We examined PKR protein expression in 55 frozen primary lung tumor tissues by Western blotting and analyzed the association between PKR expression and expresson of 139 proteins on tissue samples examined previously by Reverse Phase Protein Array (RPPA) from the same 55 patients. We observed that biomarkers were either positively (phosphorylated AMP-activated kinaseT172 [p-AMPK]) or negatively (insulin receptor substrate 1, meiotic recombination 11, ATR interacting protein, telomerase, checkpoint kinase 1, and cyclin E1) correlated with PKR. We further confirmed that induction of PKR with expression vectors in lung cancer cells causes activation of the AMPK protein independent of the LKB1, TAK1, and CaMKKβ pathway. We found that PKR causes nutrient depletion, which increases AMP levels and decreases ATP levels, causing AMPK phosphorylation. We further demonstrated that inhibiting AMPK expression with compound C or siRNA enhanced PKR-mediated cell death. We next explored the combination of PKR and p-AMPK expression in NSCLC patients and observed that expression of p-AMPK predicted a poor outcome for adenocarcinoma patients with high PKR expression and a better prognosis for those with low PKR expression. These findings were consistent with our in vitro results. AMPK might rescue cells facing metabolic stresses, such as ATP depletion caused by PKR. Our data indicate that PKR causes nutrient depletion, which induces the phosphorylation of AMPK. AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation.
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影响因子：
64.5
作者：
Leprivier G;Remke M;Rotblat B;Dubuc A;Mateo AR;Kool M;Agnihotri S;El-Naggar A;Yu B;Somasekharan SP;Faubert B;Bridon G;Tognon CE;Mathers J;Thomas R;Li A;Barokas A;Kwok B;Bowden M;Smith S;Wu X;Korshunov A;Hielscher T;Northcott PA;Galpin JD;Ahern CA;Wang Y;McCabe MG;Collins VP;Jones RG;Pollak M;Delattre O;Gleave ME;Jan E;Pfister SM;Proud CG;Derry WB;Taylor MD;Sorensen PH
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Sorensen PH
影响因子：
7.2
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11.2
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影响因子：
11.5
作者：
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影响因子：
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