| 16910777 |
Dasgupta J, Subbaram S, Connor KM, Rodriguez AM, Tirosh O, Beckman JS, Jourd'Heuil D, Melendez JA: Manganese superoxide dismutase protects from TNF-alpha-induced apoptosis by increasing the steady-state production of H2O2. Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1295-305.
Manganese superoxide dismutase (SOD2) has been well established to be essential for protection from a variety of apoptotic stimuli. Here we demonstrate that the antiapoptotic effects of SOD2 are attributed to its ability to generate H (2) O (2) and that its efficient removal resensitizes cells to tumor necrosis factor (TNF)-alpha-induced apoptosis. SOD2 overexpression in HT-1080 cells leads to a decrease in the fluorescence of the superoxidesensitive fluorophore, dihydroethidium, and a concomitant increase in oxidation of the H2O2-sensitive dye, dichlorodihydrofluorescein diacetate (DCFDA). The rate of aminotriazole-inhibited catalase activity also was increased when SOD2 is overexpressed and reflects a 1.6-fold increase in the steady-state production of H (2) O (2). The increase in H (2) O (2) was associated with decreased sensitivity to TNF-alpha-mediated apoptosis, as measured by monitoring the loss of mitochondrial membrane potential (MMP), caspase activation, poly-ADP ribose polymerase (PARP) cleavage, and accumulation of hypodiploid DNA content. Both the increase in H2O2 and resistance to TNF-mediated apoptosis were reversed by coexpression of catalase. The lipid hydroperoxide scavengers, beta-hydroxytoluene and trolox, and the iron chelator, desferroxamine, showed partial recovery of TNF-induced apoptosis. These findings indicate that increases in the intracellular steady-state production of H (2) O (2) by SOD2 can block the activation of key processes fundamental to the process of programmed cell death. |
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