Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signaling of human tumor cells.
Tumor cells are protected against intercellular reactive oxygen species (ROS)-mediated apoptosis signaling mediated by the HOCl and/or the nitric oxide (NO)/peroxynitrite signaling pathway. We have recently shown that tumor cell resistance against HOCl signaling can be abrogated through inhibition of catalase. The protection of tumor cells against the NO/peroxynitrite signaling pathway has remained enigmatic so far. Here, we show that suboptimal inhibition of catalase by 3-aminotriazole or a monoclonal antibody against catalase, as well as partial knockdown of catalase by specific siRNA allows selective reactivation of the NO/peroxynitrite pathway in MKN 45 gastric carcinoma cells, followed by the HOCl pathway at higher inhibitor or siRNA concentrations. In SKN-MC Ewing sarcoma cells, catalase inhibition causes apoptosis induction solely based on the NO/peroxynitrite pathway. Protection against NO/peroxynitrite signaling is shown to be due to the potential of catalase to decompose peroxynitrite. The direct interaction of catalase with peroxynitrite is verified through the detection of compound I (CAT Fe(IV)=O(+)*) after the interaction of peroxynitrite with catalase. In a complementary experiment, addition of catalase protects sensitive transformed cells against ROS-mediated apoptosis induction. Thus, the expression of membrane-associated catalase is sufficient to protect tumor cells against multiple intercellular ROS-mediated signaling pathways.
Heinzelmann
Sonja
S
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D-79104 Freiburg, Germany.
Bauer
Georg
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013450:Sulfones; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D002374:Catalase