Potentiation of Fas-mediated apoptosis by attenuated production of mitochondria-derived reactive oxygen species

Abstract

The role of reactive oxygen species (ROS) production in death receptor-mediated apoptosis is ill-defined. Here, we show that ROS levels play a role in moderating Fas-dependent apoptosis. Treatment of Jurkat T cells with oligomycin (ATP-synthase inhibitor) or (mitochondrial uncoupler) and Fas-activating antibody (CH11) facilitated rapid cell death that was not associated with decreased ATP production or increased DEVDase activity and cytochrome c release. However, a decrease in cellular ROS production was associated with CH11 treatment, and combinations of CH11 with oligomycin or FCCP further inhibited cellular ROS production. Thus, decreased ROS production is correlated with enhanced cell death. A transition from state 3 to state 4 mitochondrial respiration accounted for the attenuated ROS production and membrane potential. Similar observations were demonstrated in isolated rat liver mitochondria. These data show that ROS production is important in receptor-mediated apoptosis, playing a pivotal role in cell survival.

DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation

“…Our observation that NAC, MnTBAP, and C 60 (D3) did not interfere with CH11-triggered apoptosis (Figure 7) may seem contradict with the report that decreased cellular ROS production by oligomycin or FCCP enhances Fasinduced apoptosis (Aronis et al, 2003). We speculate that a reason for such discrepancy is the concentrationdependent physiological effect for ROS.…”

“…In contrast, the antioxidants used in the present study, effective in reducing stress stimulitriggered ROS burst (Alleva et al, 2001), are likely not as effective as oligomycin and FCCP in the abrogation of basal ROS production. Together, the observations that CH11-induced death is not affected by conventional antioxidants (Hug et al, 1994;Schulze-Osthoff et al, 1994;Alleva et al, 2001) and is augmented by oligomycin and FCCP (Aronis et al, 2003), suggest that intracellular basal ROS production, but not Fastriggered ROS increase, is participated in the apoptotic processes.…”

“…ROS are produced mainly in mitochondria, yet their involvement in Fas-mediated apoptosis remains unsettled. Previous studies have illustrated conflicting roles of ROS in Fas-mediated cell death, ranging from a complete dissociation from Fas-induced apoptosis (Hug et al, 1994;Schulze-Osthoff et al, 1994;Alleva et al, 2001), to a key mediator of Fas-initiated cell death (Gulbins et al, 1996;Um et al, 1996;Jayanthi et al, 1999), or to an inhibitor of Fas-triggered apoptosis (Aronis et al, 2003). The discrepancy between these studies may reflect the complicated nature of ROS and the dependence of Fas-mediated death processes on the intracellular environment.…”

“…There is a very close link between ROS production and stress-induced apoptosis (Simizu et al, 1998). In contrast, the role of ROS in Fas-induced cell death remains uncertain (Hug et al, 1994;Schulze-Osthoff et al, 1994;Gulbins et al, 1996;Um et al, 1996;Jayanthi et al, 1999;Alleva et al, 2001;Aronis et al, 2003). Mitochondria are a major source of ROS (Droge, 2002).…”

Caspase-dependent generation of reactive oxygen species in human astrocytoma cells contributes to resistance to TRAIL-mediated apoptosis

“…Although the redox state of a cell is considered to be an important determinant of its susceptibility to various apoptotic stimuli, the mechanism by which the redox state contributes to death receptor-mediated apoptosis remains unclear. Numerous reports have revealed a role for ROS as mediators of the death program, but other reports have shown that oxidative stress inhibits apoptotic signaling 13,[23][24][25] In this study, we have demonstrated that suppression of TRAIL-induced ROS levels sensitizes cells to TRAILmediated apoptosis in a caspase-dependent manner, and that this effect occurs before changes in TRAIL-induced apoptosis can be detected. These results imply that ROS can act as anti-apoptotic mediators in TRAIL-mediated signal transduction and can render tumor cells resistant to TRAIL-induced apoptosis, depending on the cellular context.…”