期刊
CANCER RESEARCH
卷 68, 期 7, 页码 2233-2240出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-5278
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- NCI NIH HHS [CA 49062, P01 CA049062, CA 11623] Funding Source: Medline
- NCRR NIH HHS [P41 RR011623] Funding Source: Medline
- NIEHS NIH HHS [R01 ES012888, ES 12888] Funding Source: Medline
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 (p) 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 degrees 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-kappa B (NF-kappa B) activation, and 2-(4-carboxyphnyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a scavenger of nitric oxide (NO), significantly decreased the mutation frequency in both bystander rho degrees and rho(+) cells. Furthermore, we found that NF-kappa B activity and its dependent proteins, cyclooxygenase-2 (COX-2) and inducible NO synthase (MOS), were lower in bystander rho degrees 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-kappa B/iNOS/NO and NF-kappa B/COX-2/prostaglandin E2 signaling pathways are important to the process.
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