Arecoline-mediated inhibition of AMP-activated protein kinase through reactive oxygen species is required for apoptosis induction
Arecoline-mediated inhibition of AMP-activated protein kinase through reactive oxygen species is required for apoptosis induction
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DOI：
10.1016/j.oraloncology.2011.02.014
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发表时间：
2011-05-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Young-Chau
中科院分区：
文献类型：
--
作者：
Yen, Ching-Yu;Lin, Mei-Huei;Liu, Young-Chau
槟榔碱是槟榔中的主要生物碱，能诱导活性氧的产生和细胞凋亡。代谢传感器AMP激活的蛋白激酶（AMPK），由ROS激活，也调节细胞凋亡。本研究以多种细胞为实验模型，分析ROS和AMPK在阿托伐他汀诱导的细胞凋亡中的作用。我们发现槟榔碱剂量依赖性地增加细胞内ROS水平，和两种抗氧化剂，N-乙酰-L-半胱氨酸（NAC）和谷胱甘肽，衰减槟榔碱诱导的细胞凋亡。有趣的是，槟榔碱剂量和时间依赖性地抑制而不是刺激AMPK-Thr（172）磷酸化，NAC和谷胱甘肽都缓解了这种抑制作用。AMPK激活剂5-氨基咪唑-4-甲酰胺1-β-D-呋喃核糖苷（AICAR）也恢复了AMPK-Thr（172）的磷酸化水平，并减弱了槟榔碱损伤下的凋亡细胞死亡。相反，AMPK抑制剂化合物C和AMPK表达的RNA干扰增加槟榔碱的细胞毒性。总的来说，这些结果表明槟榔碱可能通过细胞内ROS抑制AMPK，负责细胞凋亡的执行。(C)2011爱思唯尔有限公司版权所有。
Arecoline is the major alkaloid of areca nut (AN) and known to induce reactive oxygen species (ROS) production and apoptosis. The metabolic sensor AMP-activated protein kinase (AMPK), activated by ROS, also regulates apoptosis. This study used several types of cells as the experimental model to analyze the roles of ROS and AMPK in arecoline-induced apoptosis. We found that arecoline dose-dependently increased intracellular ROS level, and two antioxidants, N-acetyl-L-cysteine (NAC) and glutathione, attenuated arecoline-induced apoptotic cell death. Interestingly, arecoline dose-and time-dependently inhibited rather than stimulated AMPK-Thr(172) phosphorylation, and both NAC and glutathione relieved this inhibition. The AMPK activator, 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), also restored the phosphorylation level of AMPK-Thr(172) and attenuated apoptotic cell death under arecoline insult. In contrast, the AMPK inhibitor, compound C, and RNA interference of AMPK expression increased the cytotoxicity of arecoline. Collectively, these results suggest that arecoline may inhibit AMPK through intracellular ROS, responsible for the execution of apoptosis. (C) 2011 Elsevier Ltd. All rights reserved.