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Abscopal effect of low-LET γ-radiation mediated through Rel protein signal transduction in a mouse model of nontargeted radiation response

Cancer Gene Therapy volume 21, pages 54–59 (2014)Cite this article

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Abstract

Ascertaining the ionizing radiation (IR)-induced bystander response and its preceding molecular regulation would increase our understanding of the mechanism of acute and delayed radiobiological effects. Recent evidence clearly prompted that radiation-induced nuclear factor kappa B (NF-κB) would play a key role in bystander responses in nontargeted cells. Accordingly, we investigated the orchestration of NF-κB signaling after IR in a nontargeted distant organ. Heart tissues from C57/BL6 mice either mock irradiated or exposed (limited to lower abdomen 1 cm diameter) to single-dose IR (SDR: 2 or 10 Gy) or fractionated IR (FIR, 2 Gy per day for 5 days) were examined for onset of abscopal NF-κB signal transduction, translated activity, downstream functional signaling and associated DNA damage. Radiation significantly induced NF-κB DNA binding activity in nontargeted heart. Transcriptional profiling showed that 51, 46 and 26 of 88 genes were significantly upregulated after 2 Gy, 10 Gy and FIR. Of these genes, 22 showed dose- and fractionation-independent upregulation. Immunohistochemistry revealed a robust increase in p65 and cMyc expression in distant heart after SDR and FIR. Immunoblotting revealed increased phosphorylation of p38 after 2 Gy and extracellular signal-regulated kinases 1/2 after 10 Gy in nontargeted heart. In addition, IR exposure significantly enhanced DNA fragmentation in nontargeted heart. Together, these data clearly indicated an induced abscopal response in distant organ after clinically relevant IR doses. More importantly, the results imply that orchestration of NF-κB signal transduction in nontargeted tissues may serve as an effector and could play a key role in induced abscopal responses.

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Acknowledgements

We were supported by Presbyterian Health Foundation, American Cancer Society (Grant ACS-IRG-05-066-01) and National Institutes of Health (NIH-COBRE-1P20GM103639-01) to N Aravindan, and the National Institutes of Health (Grant R01 CA112175) and US Department of Energy Grant DE-FG02-03ER63449 to M Natarajan. We acknowledge Dr Salahuddin Ahmad and Mr Daniel A Johnson, Division of Radiation Physics, Department of Radiation Oncology, OUHSC, for their help in radiation dosimetry studies.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    S Aravindan, S K Ramraj, V Pandian, F H Khan, T S Herman & N Aravindan

  2. Department of Pathology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA

    M Natarajan

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  1. S Aravindan
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Correspondence to N Aravindan.

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Aravindan, S., Natarajan, M., Ramraj, S. et al. Abscopal effect of low-LET γ-radiation mediated through Rel protein signal transduction in a mouse model of nontargeted radiation response. Cancer Gene Ther 21, 54–59 (2014). https://doi.org/10.1038/cgt.2013.72

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