Fig. 1.

Intercellular apoptosis-inducing ROS signaling. (A) Transformed cells. The figure shows the membrane of a transformed cell with the intracellular space on the left side, the extracellular space on the right side. Transformed cells are defined as malignant cells that have the potential to form tumors but have not yet been confronted with the natural antitumor mechanisms of an organism. Transformed cells are characterized by expression of NOX1 that generates extracellular superoxide anions (#1). These dismutate and form H₂O₂ (2O₂^.–+2H⁺→H₂O₂+O₂) (#2) which is used by the peroxidase domain of DUOX (POD) as substrate for the generation of HOCl (H₂O₂+PODFe^III→POD Fe^IV=O^.++H₂O; POD Fe^IV=O^.++Cl^–+H⁺→PODFe^III+HOCl) (#3). HOCl interacts with superoxide anions, leading to the generation of hydroxyl radicals (HOCl+O₂^.–→.OH+O₂+Cl^–) (#4) [24,31,32] that induce lipid peroxidation (#5) and subsequent apoptosis induction through the mitochondrial pathway of apoptosis. In the presence of an high excess of H₂O₂ compared to POD, a consumption reaction between H₂O₂ and HOCl (#6) blunts HOCl signaling. The level of arginine is controlled by arginase (#7). NO synthase (NOS) utilizes arginine as substrate for the synthesis of NO (#8) [33-35]. A substantial part of NO may be converted into nitrate by NO dioxygenase (#9), which is connected to the activity of cytochrome P 450 oxidoreductase (POR). NO passes the cell membrane (#10) and reacts with superoxide anions, resulting in the formation of peroxynitrite (.NO+O₂^.–→ONOO^–) (#11) [36–40]. Protonation of peroxynitrite leads to the formation of peroxynitrous acid (ONOO^–+H⁺→ONOOH→.NO₂+.OH) (#12) [37,41–43]. As malignant cells have efficient proton pumps that establish a high local concentration of protons on the outside of their cell membrane [44], the formation of ONOOH seems to be locally favored over the competing reaction between ONOO⁻ and CO₂ (ONOO⁻ and CO₂→ONOOCOO⁻→NO₂+CO₃⁻) [45–48]. Peroxynitrous acid spontaneously decomposes into NO₂ and hydroxyl radicals (#13), which induce lipid peroxidation and the mitochondrial pathway of apoptosis (# 14). (B) Tumor cells (defined as malignant cells derived from a bona fide tumor) are protected against intercellular apoptosis-inducing ROS signaling through expression of membrane-associated catalase. Tumor progression causes the selection of a phenotype that is characterized by the expression of membrane-associated catalase [54,56]. Membrane-associated catalase protects the tumor cells against ROS signaling by the HOCl pathway (#1–#5) and the NO/peroxynitrite pathway (#6–#12) through decomposition of H₂O₂ (#13), oxidation of NO (#14) and decomposition of peroxynitrite (#15). Decomposition of H₂O₂ and peroxynitrite by catalase are two step reactions with compound I (CATFe^IV=O^.+) as intermediate. NO is oxidated to NO₂⁻ by compound I.