Iron-catalyzed antagonism between NO and H2O2 / HOCl causes mutual exclusivity of HOCl- and NO/peroxynitrite-mediated apoptosis-inducing signaling

Abstract

Membrane-associated NADPH oxidase of malignant cells drives intercellular apoptosis-inducing HOCl- and NO/peroxynitrite signaling. Cells from late stages of oncogenesis, i. e. bona fide tumor cells, interfere with these signaling pathways through expression of membrane-associated catalase. Transformed cells and tumor cells with inhibited catalase show mutual exclusivity of apoptosis-inducing NO/peroxynitrite and HOCl signaling. H2O2 is the substrate for HOCl synthesis by DUOX-coded peroxidase. However, at high concentrations of H2O2, HOCl signaling is abrogated through the reaction between excess H2O2 and HOCl. Experimental increase in the NO concentration through addition of NO donors, induction of NO synthase (NOS), addition or the NOS substrate arginine, or inhibition of NO dioxygenase(NOD) leads to the inhibition of HOCl signaling, but also to abrogation of H2O2-mediated interference with HOCl signaling. Vice versa, an increase in extracellular H2O2 through increasing the cell density, gamma irradiation or addition of glucose oxidase inhibits NO/peroxynitrite signaling. These mutual reactions between NO and H2O2/HOCl are catalyzed by an iron-mediated reaction cycle, which allows consumption of NO by H2O2/HOCl and vice versa. These reactions explain the preferences of tumor cell lines for NO/peroxynitrite or HOCl signaling after inhibition of their protective catalase, as well as the differential expression of these pathways dependent on the degree of catalase inhibition. The understanding of these reactions allows to rationally modulate quality and strength of ROS/RNS-dependent apoptosis-inducing signaling pathways of malignant cells. The knowledge about these reactions should allow to optimize strategies for tumor therapy that are based on reactivation of intercellular ROS/RNS-dependent apoptosis-inducing signaling of tumor cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/498603v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@4fbdb6org.highwire.dtl.DTLVardef@130063forg.highwire.dtl.DTLVardef@1ea2e67org.highwire.dtl.DTLVardef@18c85cb_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights* NADPH oxidase and peroxidase drive apoptosis-inducing HOCl signaling * NADPH oxidase and NO synthase drive apoptosis-inducing NO/peroxynitrite signaling * H2O2 establishes and interferes with HOCl signaling, dependent on its concentration * NO inhibits HOCl signaling and abrogates H2O2-dependent inhibition of HOCl signaling * H2O2 interferes with NO/peroxnitrite signaling * Mutual interactions of NO and H2O2 are catalysed by an iron-mediated reaction cycle