Central Signaling Elements of Intercellular Reactive Oxygen/Nitrogen Species-dependent Induction of Apoptosis in Malignant Cells.
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 through the use of specific inhibitors and scavengers. Here, a detailed analysis was carried out based on small interfering ribonucleic acid (siRNA)-mediated knockdown of central players of intercellular ROS/RNS signaling and of the mitochondrial and the FAS receptor-dependent pathway of apoptosis. The data show that transforming growth factor β1, transforming growth factor β receptor, NADPH oxidase-1 (NOX1), NOX1 organizer, and NOX1 activator control the HOCl and the NO/peroxynitrite signaling pathways. Dual oxidase-1 (DUOX1) is specifically involved in HOCl signaling, and NO synthase in NO/peroxynitrite signaling. Both pathways utilize intracellular signal transduction through protein kinase C zeta, sphingomyelinase and central elements of the mitochondrial pathway of apoptosis, whereas the FAS receptor and FAS ligand do not seem to play a role.
Institute of Virology, Medical Faculty, University Medical Center Freiburg, Freiburg, Germany georg.bauer@uniklinik-freiburg.de.
Georg
G
Bauer
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009247:NADH, NADPH Oxidoreductases
Apoptosis; HOCl signaling; NO/peroxynitrite signaling; intercellular ROS/RNS signaling; small interfering RNA