Abstract. Intercellular reactive oxygen/reactive nitrogen species-(ROS/RNS)-dependent induction of apoptosis in malignant cells is discussed as a potential control step during oncogenesis. In previous studies, the mechanism of intercellular apoptosis-inducing signaling was mainly established throughSelective induction of apoptosis in transformed cells is established either through their interaction with neighboring non-transformed cells or through autocrine apoptotic selfdestruction (1-3). Thereby, the HOCl (2, 5) and the nitric oxide/peroxynitrite (NO/PON) signaling pathways (2, 5, 6) are the dominant intercellular apoptosis-inducing signaling pathways [reviewed in (5)]. Both pathways are driven by superoxide anions which are generated by membraneassociated NADPH oxidase-1 (NOX1) of malignant cells (4, 7) and result in the generation of hydroxyl radicals that induce apoptosis through lipid peroxidation in the cell membrane (8).Mechanisms and the multiple modes of interaction of these pathways have been elucidated through inhibitor and reconstitution experiments [reviewed in (4, 5, 9)].Elimination of transformed cells through selective apoptosis induction mediated by intercellular reactive oxygen species (ROS)-dependent signaling has been discussed as a potential natural tumor-preventive mechanism (4, 10, 11). This concept is in agreement with the pioneering work of Deichman et al. , who have shown that tumor progression requires establishment of resistance to H 2 O 2 (12, 13). Resistance is achieved through the expression of membraneassociated catalase (8,14,15). Catalase interferes with the HOCl signaling pathway through decomposition of H 2 O 2 and with NO/PON signaling through oxidation of NO and decomposition of PON (5,8,16,17). Recent quantitative characterization of membrane-associated catalase has shown that localization of catalase on the outside of cells is already associated with the transformed state of the cells, however, at a concentration that is not sufficient to prevent intercellular ROS-dependent signaling (15). Catalase seems to be released by tumor cells and is covalently attached to the cells through the action of transglutaminase-2 (15).In addition to membrane-associated catalase, tumor cells also carry superoxide dismutase (SOD) on their membrane. SOD has a co-modulatory role through preventing superoxide anion-dependent inhibition of catalase (9, 18).The functional complex of membrane-associated NOX1 and protective catalase and SOD represents a regular characteristic of tumor cells and therefore is a focus for the establishment of novel therapeutic approaches (18)(19)(20). The complex signaling chemistry of transformed cells, or tumor cells after inhibition of their membrane-associated catalase, has, so far, been mainly elucidated through inhibitor studies and reconstitution experiments. Small interfering ribonucleic acid (siRNA)-based knockdown of defined 499