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Aescin-induced reactive oxygen species play a pro-survival role in human cancer cells via ATM/AMPK/ULK1-mediated autophagy

查看全文 作　　者：Bin [1]Li;Guo-liang [1]Wu;Wei [1]Dai;Gang [1]Wang;Hao-yuan [1]Su;Xue-ping [1]Shen;Rui [1]Zhan;Jia-ming [2]Xie;Zhong [2]Wang;Zheng-hong [3]Qin;Quan-gen [1]Gao;Gen-hai [1]Shen 高影响力作者 机构地区：[1]Department of General Surgery,The First People's Hospital of Wu Jiang,Suzhou 215200,China;[2]Department of General Surgery,Second Affiliated Hospital of Soochow University,Suzhou,215004Jiangsu,China;[3]Department of Pharmacology and Laboratory of Aging and Nervous Diseases,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases,College of Pharmaceutical Science,Soochow University,Suzhou 215123,China高影响力机构 出　　处：《Acta Pharmacologica Sinica》索引2018年第39卷第12期,共11页高影响力期刊 基　　金：grants from the Jiangsu Provincial Commission of Health and Family Planning (No.YG201402,YG201503);Jiangsu Provincial Medical Youth Talent,(No.QNRC2016249);Suzhou Science and Technology Bureau (No. SYSD2013041,SYSD2016044,SYSD2017041and SYS20178B);Wujiang District Science and Technology Bureau (No.WS201301);Wujiang District Commission of Health and Family Planning (No.WWK201607and WWK201609); National Natural Science Foundation of China (No.81602613). 摘　　要：Aescin, a natural mixture of triterpene saponins, has been reported to exert anticancer effect. Recent studies show that aescin increases intracellular reactive oxygen species (ROS) levels. However, whether the increased ROS play a role in the anticancer action of aescin remains to be explored. In this study, we demonstrated that aescin (20-80 μg/mL) dose-dependently induced apoptosis and activated mammalian target of rapamycin (mTOR)-independent autophagy in human hepatocellular carcinoma HepG2 cells and colon carcinoma HCT 116 cells. The activation of autophagy favored cancer cell survival in response to aescin, as suppression of autophagy with ATG5 siRNAs or 3-methyladenine (3-MA), a selective inhibitor of autophagy, promoted aescin-induced apoptosis in vitro, and significantly enhanced the anticancer effect of aescin in vivo. Meanwhile, aescin dose-dependently elevated intracellular ROS levels and activated Ataxia-telangiectasia mutated kinase/AMP-activated protein kinase/UNC-51-like kinase-1 (ATM/AMPK/ULK1) pathway. The ROS and ATM/AMPK/ULK1 pathway were upstream modulators of the aescin-induced autophagy, as N-acetyl-L-cysteine (NAC) or ATM kinase inhibitor (KU-55933) remarkably suppressed aescin-induced autophagy and consequently promoted aescin-induced apoptosis, whereas overexpression of ATG5 partly attenuated NAC-induced enhancement in aescin-induced apoptosis. In conclusion, this study provides new insights into the roles of aescin-mediated oxidative stress and autophagy in cancer cell survival. Our results suggest that combined administration of the antioxidants or autophagic inhibitors with aescin might be a potential strategy to enhance the anticancer effect of aescin. 关 键 词：AESCIN ROS AUTOPHAGY apoptosis HUMAN hepatocellular CARCINOMA HepG2 CELLS HUMAN colon CARCINOMA HCT 116 CELLS 3-MA NAC KU-55933
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