Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects.
Although radiation-induced bystander effects have been well described over the past decade, the mechanisms of the signaling processes involved in the bystander phenomenon remain unclear. In the present study, using the Columbia University charged particle microbeam, we found that mitochondrial DNA-depleted human skin fibroblasts (rho(o)) showed a higher bystander mutagenic response in confluent monolayers when a fraction of the same population were irradiated with lethal doses compared with their parental mitochondrial-functional cells (rho(+)). However, using mixed cultures of rho(o) and rho(+) cells and targeting only one population of cells with a lethal dose of alpha-particles, a decreased bystander mutagenesis was uniformly found in nonirradiated bystander cells of both cell types, indicating that signals from one cell type can modulate expression of bystander response in another cell type. In addition, we found that Bay 11-7082, a pharmacologic inhibitor of nuclear factor-kappaB (NF-kappaB) activation, and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a scavenger of nitric oxide (NO), significantly decreased the mutation frequency in both bystander rho(o) and rho(+) cells. Furthermore, we found that NF-kappaB activity and its dependent proteins, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), were lower in bystander rho(o) cells when compared with their rho(+) counterparts. Our results indicated that mitochondria play an important role in the regulation of radiation-induced bystander effects and that mitochondria-dependent NF-kappaB/iNOS/NO and NF-kappaB/COX-2/prostaglandin E2 signaling pathways are important to the process.
Zhou
Hongning
H
Center for Radiological Research, College of Physicians and Surgeons, Mailman School of Public Health, Columbia University, New York, NY, USA.
Ivanov
Vladimir N
VN
Lien
Yu-Chin
YC
Davidson
Mercy
M
Hei
Tom K
TK
D000512:Alpha Particles; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002450:Cell Communication / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D016296:Mutagenesis / Q000187:drug effects / Q000528:radiation effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D013450:Sulfones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000911:Antibodies, Monoclonal; D001565:Benzoates; D004272:DNA, Mitochondrial; D007093:Imidazoles; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D007041:Hypoxanthine Phosphoribosyltransferase