Reactive oxygen species generated in different compartments induce cell death, survival, or senescence
Emiliano Panieri1, Vladimir Gogvadze, Erik Norberg
1Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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.
Insights
Reactive oxygen species (ROS) dictate cell fate based on their concentration and location. Understanding ROS generation is key for developing effective anticancer therapies targeting non-small-cell lung cancer.
Area of Science:
- Cellular Biology
- Biochemistry
- Oncology
Background:
- Reactive oxygen species (ROS) are crucial in oxidative damage and cell death.
- Anticancer therapies often rely on ROS production for tumor eradication.
- Mechanisms linking ROS to specific cell death and their spatiotemporal requirements remain unclear.
Purpose of the Study:
- To investigate how the site of ROS production and accumulation influences cell fate in non-small-cell lung cancer (NSCLC).
- To elucidate the distinct cellular responses to varying concentrations and locations of ROS.
Main Methods:
- Utilized multiple non-small-cell lung cancer cell lines.
- Manipulated exogenous and endogenous (mitochondrial) hydrogen peroxide (H2O2) levels.
- Assessed DNA damage, ATP levels, cytotoxicity, cell cycle progression, and senescence.
- Investigated the role of RIP1 kinase inhibition and glycolysis inhibition.
Main Results:
- High exogenous H2O2 caused DNA damage, ATP depletion, and cytotoxicity, partially preventable by RIP1 kinase inhibition.
- Low exogenous H2O2 induced G2/M arrest and senescence with delayed toxicity.
- Mitochondrial H2O2 led to G1/S arrest and senescence, with reversible ATP drop and no impact on viability.
- Glycolysis inhibition sensitized cells to ROS-induced death.
Conclusions:
- ROS concentration and site of generation critically determine cellular outcomes, including cell death, arrest, and senescence.
- Findings offer insights into optimizing ROS-based anticancer strategies.
- The interplay between ROS, ATP levels, and metabolic pathways influences cell fate decisions.
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