Fig. 14.

Mechanism of bystander signaling of tumor cells after treatment with H₂O₂ and nitrite. First steps. A. The membrane of tumor cells carries active NADPH oxidase-1 (NOX1) (#1) that generates extracellular superoxide anions (#2). NO synthase (NOS) (#3) generates NO that passes through the membrane. Membrane-associated catalase (#4) protects the tumor cells towards HOCl and NO/peroxynitrite signaling through decomposition of H₂O₂ and peroxynitrite. Oxidation of NO by catalase as well as the comodulatory activity of membrane-associated SOD that prevents superoxide anion-dependent inhibition of catalase is not shown in the Figure for simplicity. The figure shows the FAS receptor (#5), caspase-8 (#6) and proton pumps (#7). Long-lived species H₂O₂ and nitrite from CAP or PAM (#8) interact and generate primary singlet oxygen (#9 - #11) (simplified scheme, please see Fig. 16 for more details). B. Primary singlet oxygen (#1) causes local inactivation of catalase (#2). As a result, cell-derived H₂O₂ and peroxynitrite are not decomposed at that site and may form secondary singlet oxygen (#3, #4). The full complexity of reaction #3 is shown in Fig. 16. Secondary singlet oxygen inactivates further catalase molecules (#5, #6) or activates the FAS receptor (#7). This leads to the activation of caspase-8 (#8) and subsequent activation of NOX1 (#9) and enhancement of NOS expression (#10).