BACKGROUND: Oncogenic transformation depends on the activation of membrane-associated @entity1110 oxidase. The resultant extracellular @entity224 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/ @entity6710 pathway. @entity5 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 @entity5568 and with NO/ @entity6710 through oxidation of NO and decomposition of @entity6710 . AIMS: We aimed to establish the biochemical basis for novel therapeutic approaches that target @entity5 cell protective catalase and thus cause reactivation of intercellular reactive @entity26 / @entity1568 species-dependent apoptotic signaling of @entity5 cells. METHODS: We used cells from defined stages of multistep oncogenesis, i. e. nontransformed, transformed and bona vide @entity5 cells. Intercellular apoptosis-inducing ROS/RNS signaling was studied using defined inhibitors/scavengers, reconstitution experiments and small interfering RNA directed against relevant targets. RESULTS: Direct inhibition of @entity5 cell catalase by neutralizing antibodies or its direct inactivation by extracellular singlet @entity26 caused efficient reactivation of apoptosis-inducing signaling. Interestingly, the increase in cell-derived NO through addition of @entity369 , inhibition of arginase, inhibition of NO dioxygenase or induction of NO synthase by interferon led to the generation of extracellular singlet @entity26 that triggered a complex self-amplificatory system. As a result, high concentrations of cell-derived singlet @entity26 inactivated catalase and reactivated apoptosis inducing intercellular signaling. CONCLUSIONS: Modulation of the cellular NO concentration causes extracellular singlet @entity26 generation and inactivation of @entity5 cell protective catalase.

Synergistic Interactions Between Nitric Oxide And Reactive XXXX Species Cause Selective Apoptosis Induction In Malignant Cells.

@entity5568 :: ('D006861', 'Chemical') :: ['H2O2'] @entity1568 :: ('MESH:D009584', 'Chemical') :: ['nitrogen'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'Tumor'] @entity26 :: ('MESH:D010100', 'Chemical') :: ['oxygen'] @entity1110 :: ('MESH:D009249', 'Chemical') :: ['NADPH'] @entity6710 :: ('MESH:D030421', 'Chemical') :: ['peroxynitrite'] @entity224 :: ('MESH:D013481', 'Chemical') :: ['superoxide'] @entity369 :: ('CHEBI:29016', 'Chemical') :: ['arginine']
@entity26 :: (MESH:D010100,Chemical) :: ['Oxygen']
