Increasing the endogenous NO level causes catalase inactivation and reactivation of intercellular apoptosis signaling specifically in tumor cells.
Tumor cells generate extracellular superoxide anions and are protected against intercellular apoptosis-inducing HOCl- and NO/peroxynitrite signaling through the expression of membrane-associated catalase. This enzyme decomposes H2O2 and thus prevents HOCl synthesis. It efficiently interferes with NO/peroxynitrite signaling through oxidation of NO and decomposition of peroxynitrite. The regulatory potential of catalase at the crosspoint of ROS and RNS chemical biology, as well as its high local concentration on the outside of the cell membrane of tumor cells, establish tight control of intercellular signaling and thus prevent tumor cell apoptosis. Therefore, inhibition of catalase or its inactivation by singlet oxygen reactivate intercellular apoptosis-inducing signaling. Nitric oxide and peroxynitrite are connected with catalase in multiple and meaningful ways, as (i) NO can be oxidated by compound I of catalase, (ii) NO can reversibly inhibit catalase, (iii) peroxynitrite can be decomposed by catalase and (iv) the interaction between peroxynitrite and H2O2 leads to the generation of singlet oxygen that inactivates catalase. Therefore, modulation of the concentration of free NO through addition of arginine, inhibition of arginase, induction of NOS expression or inhibition of NO dioxygenase triggers an autoamplificatory biochemical cascade that is based on initial formation of singlet oxygen, amplification of superoxide anion/H2O2 and NO generation through singlet oxygen dependent stimulation of the FAS receptor and caspase-8. Finally, singlet oxygen is generated at sufficiently high concentration to inactivate protective catalase and to reactivate intercellular apoptosis-inducing ROS signaling. This regulatory network allows to establish several pathways for synergistic interactions, like the combination of modulators of NO metabolism with enhancers of superoxide anion generation, modulators of NO metabolism that act at different targets and between modulators of NO metabolism and direct catalase inhibitors. The latter aspect is explicitely studied for the interaction between catalase inhibiting acetylsalicylic acid and an NO donor. It is also shown that hybrid molecules like NO-aspirin utilize this synergistic potential. Our data open novel approaches for rational tumor therapy based on specific ROS signaling and its control in tumor cells.
Institute of Virology, Department of Medical Microbiology and Hygiene, University Medical Center Freiburg, Hermann-Herder Strasse 11, D-79104 Freiburg, Germany. Electronic address: georg.bauer@uniklinik-freiburg.de.
Georg
G
Bauer
D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology; D002374:Catalase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism; D017494:Proton Pumps / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D026082:Singlet Oxygen / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D008665:Metalloporphyrins; C488176:N-acetyl-S-(alpha-methyl-4-(2-methylpropyl)benzeneacetyl)cysteine 4-(nitrooxy)butyl ester; D009566:Nitrates; D017494:Proton Pumps; D019014:fas Receptor; D030421:Peroxynitrous Acid; D026082:Singlet Oxygen; D009569:Nitric Oxide; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D001241:Aspirin
Catalase; Intercellular apoptosis-inducingsignaling; Nitric oxide; Peroxynitrite; Singlet oxygen; Synergistic effect