Abstract
Reactive oxygen species (ROS)-induced apoptosis has been extensively studied. Increasing evidence suggests that ROS, for instance, induced by hydrogen peroxide (H2O2), might also trigger regulated necrotic cell death pathways. Almost nothing is known about the cell death pathways triggered by tertiary-butyl hydroperoxide (t-BuOOH), a widely used inducer of oxidative stress. The lipid peroxidation products induced by t-BuOOH are involved in the pathophysiology of many diseases, such as cancer, cardiovascular diseases, or diabetes. In this study, we exposed murine fibroblasts (NIH3T3) or human keratinocytes (HaCaT) to t-BuOOH (50 or 200 μM, respectively) which induced a rapid necrotic cell death. Well-established regulators of cell death, i.e., p53, poly(ADP)ribose polymerase-1 (PARP-1), the stress kinases p38 and c-Jun N-terminal-kinases 1/2 (JNK1/2), or receptor-interacting serine/threonine protein kinase 1 (RIPK1) and 3 (RIPK3), were not required for t-BuOOH-mediated cell death. Using the selective inhibitors ferrostatin-1 (1 μM) and liproxstatin-1 (1 μM), we identified ferroptosis, a recently discovered cell death mechanism dependent on iron and lipid peroxidation, as the main cell death pathway. Accordingly, t-BuOOH exposure resulted in a ferrostatin-1- and liproxstatin-1-sensitive increase in lipid peroxidation and cytosolic ROS. Ferroptosis was executed independently from other t-BuOOH-mediated cellular damages, i.e., loss of mitochondrial membrane potential, DNA double-strand breaks, or replication block. H2O2 did not cause ferroptosis at equitoxic concentrations (300 μM) and induced a (1) lower and (2) ferrostatin-1- or liproxstatin-1-insensitive increase in lipid peroxidation. We identify that t-BuOOH and H2O2 produce a different pattern of lipid peroxidation, thereby leading to different cell death pathways and present t-BuOOH as a novel inducer of ferroptosis.
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Acknowledgements
We thank Bernd Epe for fruitful discussions. We are indebted to Anna Frumkina for expert technical assistance. The technical support by Julia Altmaier, FACS, and Array Core Facility is gratefully acknowledged. The work was supported by the Stipendienstiftung Rheinland-Pfalz, Hoffmann-Klose-Stiftung, Johannes Gutenberg-University, and University Medical Center of the Johannes Gutenberg-University and is part of the Ph.D. thesis of CW and the MD theses of BL, CT, and ASS. SK acknowledges support from Dr. Werner Jackstädt-Stiftung and Fresenius Medical Care Germany.
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Wenz, C., Faust, D., Linz, B. et al. t-BuOOH induces ferroptosis in human and murine cell lines. Arch Toxicol 92, 759–775 (2018). https://doi.org/10.1007/s00204-017-2066-y
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DOI: https://doi.org/10.1007/s00204-017-2066-y