Reactive oxygen species generated in different compartments induce cell death, survival, or senescence

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• 作者：Emiliano Panieri ; Vladimir Gogvadze ; Erik Norberg¹ ; Rithika Venkatesh ; Sten Orrenius ; Boris Zhivotovsky ; ^{Boris.Zhivotovsky@ki.se}
• 关键词：AMA ; antimycin A ; 2-DG ; 2-deoxyglucose ; Necr-1 ; necrostatin&ndash ; 1 ; NSCLC ; non-small-cell lung carcinoma ; ROS ; reactive oxygen species ; X/XH ; xanthine oxidase/xanthine high concentration ; X/XL ; xanthine oxidase/xanthine low concentration
• 刊名：Free Radical Biology and Medicine
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：57
• 期：Complete
• 页码：176-187
• 全文大小：2275 K

文摘

Although reactive oxygen species (ROS) are well-established mediators of oxidative damage and cell demise, the mechanisms by which they trigger specific cell death modalities and the temporal/spatial requirements underlying this phenomenon are largely unknown. Yet, it is well established that most anticancer therapies depend on ROS production for efficient tumor eradication. Using several non-small-cell lung cancer cell lines, we have dissected how the site of ROS production and accumulation in various cell compartments affect cell fate. We demonstrate that high levels of exogenously generated H₂O₂ induce extensive DNA damage, ATP depletion, and severe cytotoxicity. Although these effects were independent of caspase activity, they could¡ªat least in part¡ªbe prevented by RIP1 kinase inhibition. In contrast, low levels of exogenously produced H₂O₂ triggered a modest drop in ATP level, delayed toxicity, G2/M arrest, and cell senescence. Mitochondrially produced H₂O₂ induced a reversible ATP drop without affecting cell viability. Instead, the cells accumulated in the G1/S phase of the cell cycle and became senescent. Concomitant inhibition of glycolysis was found to markedly sensitize cells to death in the presence of otherwise nontoxic concentrations of H₂O₂, presumably by the inhibition of ATP-restoring mechanisms. Combined, our data provide evidence that ROS might dictate different cellular consequences depending on their overall concentration at steady-state levels and on their site of generation.