Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells
Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells
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DOI：
10.1038/sj.cdd.4402233
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发表时间：
2008-01-01
影响因子：
12.4
通讯作者：
Gibson, S. B.
中科院分区：
文献类型：
--
作者：
Chen, Y.;McMillan-Ward, E.;Gibson, S. B.
自噬是一种自我消化过程，其降解细胞内结构以响应导致细胞存活的应激。当自噬延长时，这可能导致细胞死亡。通过氧化应激产生活性氧（ROS）导致细胞死亡。自噬在氧化应激诱导的细胞死亡中的作用尚不清楚。在这项研究中，我们报告了两种ROS生成剂，过氧化氢（H2 O2）和2-甲氧基乙醇（2-ME），诱导自噬的转化细胞系HEK 293和癌细胞系U87和HeLa。使用抑制剂3-甲基腺嘌呤或针对自噬基因的小干扰RNA（beclin-1、atg-5和atg-7）阻断这种自噬反应可抑制H2 O2或2-ME诱导的细胞死亡。H2 O2和2-ME也诱导细胞凋亡，但使用半胱天冬酶抑制剂zVAD-氟甲基酮（benzyloxycarbonyl-Val-Ala-Aspfluoromethylketone）阻断细胞凋亡未能抑制自噬和细胞死亡，这表明自噬诱导的细胞死亡独立于细胞凋亡发生。通过过表达锰超氧化物歧化酶或ROS清除剂4，5-二羟基-1，3-苯二磺酸二钠盐阻断H2 O2或2-ME诱导的ROS产生可减少自噬和细胞死亡。阻断自噬不影响H2 O2或2-ME诱导的ROS产生，表明ROS产生发生在自噬的上游。相反，H2 O2或2-ME未能显着增加小鼠星形胶质细胞的自噬。两者合计，ROS诱导自噬细胞死亡的转化和癌细胞，但未能诱导自噬细胞死亡的非转化细胞。
Autophagy is a self-digestion process that degrades intracellular structures in response to stresses leading to cell survival. When autophagy is prolonged, this could lead to cell death. Generation of reactive oxygen species (ROS) through oxidative stress causes cell death. The role of autophagy in oxidative stress-induced cell death is unknown. In this study, we report that two ROS-generating agents, hydrogen peroxide (H2O2) and 2-methoxyestradiol (2-ME), induced autophagy in the transformed cell line HEK293 and the cancer cell lines U87 and HeLa. Blocking this autophagy response using inhibitor 3-methyladenine or small interfering RNAs against autophagy genes, beclin-1, atg-5 and atg-7 inhibited H2O2 or 2-ME-induced cell death. H2O2 and 2-ME also induced apoptosis but blocking apoptosis using the caspase inhibitor zVAD-fmk (benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone) failed to inhibit autophagy and cell death suggesting that autophagy-induced cell death occurred independent of apoptosis. Blocking ROS production induced by H2O2 or 2-ME through overexpression of manganese-superoxide dismutase or using ROS scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid-disodium salt decreased autophagy and cell death. Blocking autophagy did not affect H2O2-or 2-ME-induced ROS generation, suggesting that ROS generation occurs upstream of autophagy. In contrast, H2O2 or 2-ME failed to significantly increase autophagy in mouse astrocytes. Taken together, ROS induced autophagic cell death in transformed and cancer cells but failed to induce autophagic cell death in nontransformed cells.