Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts.
Oncogenic transformed fibroblasts are characterized by extracellular superoxide anion generation through a membrane-associated NADPH oxidase. After cellular glutathione depletion, extracellular reactive oxygen species (ROS) generated by transformed fibroblasts exhibit a strong apoptosis-inducing potential. As apoptosis induction under glutathione depletion is inhibited by catalase, the NADPH oxidase inhibitor apocynin, superoxide dismutase, the hydroxyl radical scavenger terephthalate and the iron chelator deferoxamine, the metal-catalysed Haber-Weiss reaction seems to be the responsible signaling mechanism. In contrast to extracellular ROS, intracellular ROS play no role for apoptosis induction in glutathione-depleted transformed fibroblasts initially, since a high level of intracellular catalase scavenges intracellular hydrogen peroxide. Intracellular catalase seems to be induced by extracellular hydrogen peroxide, as pretreatment of transformed fibroblasts with exogenous catalase downmodulates endogenous catalase and renders glutathione-depleted transformed cells susceptible for the effect of endogenous hydrogen peroxide. In contrast to transformed fibroblasts, nontransformed glutathione-depleted fibroblasts do not generate substantial extracellular ROS, but apoptosis is efficiently induced in these cells by intracellular ROS. Our data show that extracellular ROS of transformed fibroblasts exhibit redox-related signaling and at the same time represent a potential apoptosis-inducing hazard through the metal-catalysed Haber-Weiss reaction.
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Germany.
Mareike
M
Schimmel
Georg
G
Bauer
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D010084:Oxidation-Reduction; D010795:Phthalic Acids / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D000098:Acetophenones; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D010795:Phthalic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; C011363:terephthalic acid; C056165:acetovanillone; D002374:Catalase; D013482:Superoxide Dismutase; D018631:ras Proteins; D005978:Glutathione; D003676:Deferoxamine