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Differential effects of Bcl-2 and caspases on mitochondrial permeabilization during endogenous or exogenous reactive oxygen species-induced cell death: A comparative study of H 2 O 2 , paraquat, t-BHP, etoposide and TNF-α-induced cell death

Abstract : In this study, we have compared several features of cell death triggered by classical inducers of apoptotic pathways (etoposide and tumour necrosis factor (TNF)-α) versus exogenous reactive oxygen species (ROS; hydrogen peroxide (H 2 O 2), tert-butyl hydroper-oxide (t-BHP)) or a ROS generator (paraquat). Our aim was to characterize relationships that exist between ROS, mitochondrial perturbations, Bcl-2 and caspases, depending on source and identity of ROS. First, we have found that these five inducers trigger oxidative stress, mitochondrial membrane permeabilization (MMP), cy-tochrome c (cyt c) release from mitochondria and cell death. In each case, cell death could be inhibited by several antioxidants, showing that it is primarily ROS dependent. Second, we have highlighted that during etoposide or TNF-α treatments, intracellular ROS level, MMP and cell death are all regulated by caspases and Bcl-2, with caspases acting early in the process. Third, we have demonstrated that H 2 O 2-induced cell death shares many of these characteristics with etoposide and TNF-α, whereas t-BHP induces both caspase-dependent and caspase-independent cell death. Surprisingly , paraquat-induced cell death, which harbours some characteristics of apoptosis such as cyt c release and caspase-3 activation, is not modulated by Bcl-2 and caspase inhibitors, suggesting that paraquat also triggers non-apoptotic cell death signals. On the one hand, these results show that endogenous or exogenous ROS can trigger multiple cell death pathways with Bcl-2 and caspases acting differentially. On the other hand, they suggest that H 2 O 2 could be an important mediator of etoposide and TNF-α-dependent cell death since these inducers trigger similar phenotypes.
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https://hal.uvsq.fr/hal-02977712
Contributor : Bernard Mignotte Connect in order to contact the contributor
Submitted on : Monday, October 26, 2020 - 5:48:45 PM
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Vincent Rincheval, Marie Bergeaud, Lise Mathieu, Jacqueline Leroy, Arnaud Guillaume, et al.. Differential effects of Bcl-2 and caspases on mitochondrial permeabilization during endogenous or exogenous reactive oxygen species-induced cell death: A comparative study of H 2 O 2 , paraquat, t-BHP, etoposide and TNF-α-induced cell death. Cell Biology and Toxicology, Springer Verlag, 2012, 28, pp.239-253. ⟨10.1007/s10565-012-9219-9⟩. ⟨hal-02977712⟩

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