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首页> 外文期刊>Radiotherapy and oncology: Journal of the European Society for Therapeutic Radiology and Oncology >AMPK regulates metabolism and survival in response to ionizing radiation.
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AMPK regulates metabolism and survival in response to ionizing radiation.

机译：AMPK响应电离辐射调节新陈代谢和存活。

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摘要

BACKGROUND AND PURPOSE: AMPK is a metabolic sensor and an upstream inhibitor of mTOR activity. AMPK is phosphorylated by ionizing radiation (IR) in an ATM dependent manner, but the cellular consequences of this phosphorylation event have remained unclear. The objective of this study was to assess whether AMPK plays a functional role in regulating cellular responses to IR. METHODS: The importance of AMPK expression for radiation responses was investigated using both MEFs (mouse embryo fibroblasts) double knockout for AMPK alpha1/alpha2 subunits and human colorectal carcinoma cells (HCT 116) with AMPK alpha1/alpha2 shRNA mediated knockdown. RESULTS: We demonstrate here that IR results in phosphorylation of both AMPK and its substrate, ACC. IR moderately stimulated mTOR activity, and this was substantially exacerbated in the absence of AMPK. AMPK was required for IR induced expression of the mTOR inhibitor REDD1, indicating that AMPK restrains mTOR activity through multiple mechanisms. Likewise, cellular metabolism was deregulated following irradiation in the absence of AMPK, as evidenced by a substantial increase in oxygen consumption rates and lactate production. AMPK deficient cells showed impairment of the G1/S cell cycle checkpoint, and were unable to support long-term proliferation during starvation following radiation. Lastly, we show that AMPK proficiency is important for clonogenic survival after radiation during starvation. CONCLUSIONS: These data reveal novel functional roles for AMPK in regulating mTOR signaling, cell cycle, survival and metabolic responses to IR.
机译：背景与目的：AMPK是一种代谢传感器，是mTOR活性的上游抑制剂。 AMPK通过依赖ATM的电离辐射（IR）进行磷酸化，但是这种磷酸化事件的细胞后果仍然不清楚。这项研究的目的是评估AMPK是否在调节细胞对IR的反应中发挥功能性作用。方法：使用AMPK alpha1 / alpha2亚基的MEF（小鼠胚胎成纤维细胞）双重敲除和带有AMPK alpha1 / alpha2 shRNA介导的人大肠癌细胞（HCT 116），研究了AMPK表达对于放射反应的重要性。结果：我们在这里证明IR导致AMPK及其底物ACC磷酸化。 IR适度地刺激了mTOR活性，并且在不存在AMPK的情况下这大大加剧了。 IR诱导mTOR抑制剂REDD1的表达需要AMPK，这表明AMPK通过多种机制抑制mTOR活性。同样，在不存在AMPK的情况下，辐照后细胞的新陈代谢也被解除，这是由耗氧率和乳酸生成的大幅增加所证明的。缺乏AMPK的细胞显示G1 / S细胞周期检查点受损，并且在辐射后饥饿期间无法支持长期增殖。最后，我们表明AMPK水平对于饥饿期间放疗后的克隆形成存活很重要。结论：这些数据揭示了AMPK在调节mTOR信号传导，细胞周期，存活和对IR的代谢反应中的新功能作用。

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