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Life Sci Space Res (Amst). 2015 Jul;6:36-43. doi: 10.1016/j.lssr.2015.06.004. Epub 2015 Jun 25.

Nitric oxide-mediated bystander signal transduction induced by heavy-ion microbeam irradiation.

Author information

1
Radiation Safety Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado Kita, Komae, Tokyo 201-8511, Japan. Electronic address: mstomita@criepi.denken.or.jp.
2
Division of Oncology, Biomedical Imaging Research Center, University of Fukui, 23-3 Matsuoka-Shimoaitsuki, Eiheiji-cho, Fukui 910-1193, Japan.
3
Microbeam Radiation Biology Group, Radiation Biology Research Division, Quantum Beam Science Center, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki, Gunma 370-1292, Japan.
4
Radiation Safety Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado Kita, Komae, Tokyo 201-8511, Japan.
5
Radiation Safety Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado Kita, Komae, Tokyo 201-8511, Japan; Proton Medical Research Group, Research and Development Department, The Wakasa Wan Energy Research Center, 64-52-1 Nagatani, Tsuruga-shi, Fukui 914-0192, Japan.

Abstract

In general, a radiation-induced bystander response is known to be a cellular response induced in non-irradiated cells after receiving bystander signaling factors released from directly irradiated cells within a cell population. Bystander responses induced by high-linear energy transfer (LET) heavy ions at low fluence are an important health problem for astronauts in space. Bystander responses are mediated via physical cell-cell contact, such as gap-junction intercellular communication (GJIC) and/or diffusive factors released into the medium in cell culture conditions. Nitric oxide (NO) is a well-known major initiator/mediator of intercellular signaling within culture medium during bystander responses. In this study, we investigated the NO-mediated bystander signal transduction induced by high-LET argon (Ar)-ion microbeam irradiation of normal human fibroblasts. Foci formation by DNA double-strand break repair proteins was induced in non-irradiated cells, which were co-cultured with those irradiated by high-LET Ar-ion microbeams in the same culture plate. Foci formation was suppressed significantly by pretreatment with an NO scavenger. Furthermore, NO-mediated reproductive cell death was also induced in bystander cells. Phosphorylation of NF-κB and Akt were induced during NO-mediated bystander signaling in the irradiated and bystander cells. However, the activation of these proteins depended on the incubation time after irradiation. The accumulation of cyclooxygenase-2 (COX-2), a downstream target of NO and NF-κB, was observed in the bystander cells 6 h after irradiation but not in the directly irradiated cells. Our findings suggest that Akt- and NF-κB-dependent signaling pathways involving COX-2 play important roles in NO-mediated high-LET heavy-ion-induced bystander responses. In addition, COX-2 may be used as a molecular marker of high-LET heavy-ion-induced bystander cells to distinguish them from directly irradiated cells, although this may depend on the time after irradiation.

KEYWORDS:

Bystander response; Heavy ion; Microbeam; Nitric oxide; Non-targeted effect

PMID:
26256626
DOI:
10.1016/j.lssr.2015.06.004
[Indexed for MEDLINE]

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