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Mitochondrial Function and Nuclear Factor-B–Mediated Signaling in Radiation-Induced Bystander Effects

¹ Center for Radiological Research, ² Department of Neurology, College of Physicians and Surgeons, and ³ Department of Environmental Health Science, Mailman School of Public Health, Columbia University, New York, New York

Requests for reprints: Tom K. Hei, Center for Radiological Research, Columbia University Medical Center, 168 West 168th Street, VC 11-204, New York, NY 10032. Phone: 212-305-8462; Fax: 212-305-3229; E-mail: tkh1{at}columbia.edu.

Key Words: Rho zero cells • mitochondrial function • radiation-induced bystander effect • NF-B • nitric oxide • cyclooxygenase-2

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 (^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 (⁺). However, using mixed cultures of ^o and ⁺ cells and targeting only one population of cells with a lethal dose of -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-B (NF-B) 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 ^o and ⁺ cells. Furthermore, we found that NF-B activity and its dependent proteins, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), were lower in bystander ^o cells when compared with their ⁺ counterparts. Our results indicated that mitochondria play an important role in the regulation of radiation-induced bystander effects and that mitochondria-dependent NF-B/iNOS/NO and NF-B/COX-2/prostaglandin E2 signaling pathways are important to the process. [Cancer Res 2008;68(7):2233–40]