Nitric Oxide's Contribution to Selective Apoptosis Induction in Malignant Cells through Multiple Reaction Steps

Nitric oxide (NO) induces apoptosis selectively in NADPH oxidase-1-expressing malignant cells through peroxynitrite formation after the interaction of NO with extracellular superoxide anions. Membrane-associated proton pumps ensure the protonation of peroxynitrite, followed by decomposition into NO2 and hydroxyl radicals that cause lipid peroxidation and thus trigger the mitochondrial pathway of apoptosis. Distant from the cell membrane, NO is oxidized by oxygen, whereas peroxynitrite preferentially reacts with CO2. These consumption reactions attenuate apoptosis-inducing NO/peroxynitrite signaling. There is mutual interference between NO/peroxynitrite and HOCl signaling, based on complex NO/H2O2 interactions. Tumor progression leads to resistance of tumor cells against NO/peroxynitrite-dependent signaling through expression of membrane-associated catalase that oxidizes NO and decomposes peroxynitrite. There is a fine-tuned balance between catalase-mediated oxidation of NO and NO-dependent inhibition of catalase. Increasing the NO concentration through enhancement of NOS activity or inhibition of NO dioxygenase causes local inhibition of catalase. Then the interaction between free peroxynitrite and H2O2 allows the generation of singlet oxygen, which inactivates additional catalase molecules, allowing for the generation of additional singlet oxygen. Alternatively, singlet oxygen may activate the FAS receptor and thus cause enhancement of NOX1 activity and NOS expression. This leads to an autoamplificatory enhancement of catalase inactivation, followed by intercellular ROS/RNS-mediated apoptosis-inducing signaling. In addition, the signaling molecules HOCl and peroxynitrite seem to trigger immunogenic cell death and thus might establish a beneficial cytotoxic T cell response.