Synergistic Interactions Between Nitric Oxide And Reactive Oxygen Species Cause Selective Apoptosis Induction In Malignant Cells.
Oncogenic transformation depends on the activation of membrane-associated NADPH oxidase. The resultant extracellular superoxide anions control the proliferation of malignant cells, but they also drive two intercellular signaling pathways that cause selective apoptosis induction in malignant cells, i. e. the HOCl and the NO/peroxynitrite pathway. Tumor progression requires the establishment of resistance against these apoptosis-inducing pathways through expression of membrane-associated catalase that interferes with HOCl signaling through decomposition of H2O2and with NO/peroxynitrite through oxidation of NO and decomposition of peroxynitrite.



We aimed to establish the biochemical basis for novel therapeutic approaches that target tumor cell protective catalase and thus cause reactivation of intercellular reactive oxygen/nitrogen species-dependent apoptotic signaling of tumor cells.



We used cells from defined stages of multistep oncogenesis, i. e. nontransformed, transformed and bona vide tumor cells. Intercellular apoptosis-inducing ROS/RNS signaling was studied using defined inhibitors/scavengers, reconstitution experiments and small interfering RNA directed against relevant targets.



Direct inhibition of tumor cell catalase by neutralizing antibodies or its direct inactivation by extracellular singlet oxygen caused efficient reactivation of apoptosis-inducing signaling. Interestingly, the increase in cell-derived NO through addition of arginine, inhibition of arginase, inhibition of NO dioxygenase or induction of NO synthase by interferon led to the generation of extracellular singlet oxygen that triggered a complex self-amplificatory system. As a result, high concentrations of cell-derived singlet oxygen inactivated catalase and reactivated apoptosis inducing intercellular signaling.



Modulation of the cellular NO concentration causes extracellular singlet oxygen generation and inactivation of tumor cell protective catalase.
Institute of Virology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany.
Georg
G
Bauer
D000818:Animals; D017209:Apoptosis; D002374:Catalase / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D010472:Perchlorates / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D015398:Signal Transduction
D009363:Neoplasm Proteins; D010472:Perchlorates; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D002374:Catalase; C494474:perchlorate