title: Reactive oxygen species generated in different compartments induce cell death, survival, or senescence.
abstract: 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-at least in part-be 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.
authors.affiliation: Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Panieri
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
authors.forename: Erik
authors.initials: E
authors.lastname: Norberg
authors.forename: Rithika
authors.initials: R
authors.lastname: Venkatesh
authors.forename: Sten
authors.initials: S
authors.lastname: Orrenius
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D002470:Cell Survival; D016922:Cellular Senescence; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints; D006019:Glycolysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008175:Lung Neoplasms; D008928:Mitochondria / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C119724:AGFG1 protein, human; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide