In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 486-486
Abstract:
Ascertaining the ionizing radiation (IR)-induced bystander response and identifying its mechanistic regulation would raise a paradigm shift in our understanding of the radiobiological effects. Recent evidence from our lab and others clearly prompted that the transcriptional regulator NFκB would play a key role in induced responses in non-targeted bystander cells. In this study, for the first time, we investigated the orchestration of NFκB signaling after IR in an organ (heart) distant from the exposure field. The C57/BL6 mice either mock irradiated, exposed to single dose IR (SDR: 2 or 10Gy) or fractionated IR (FIR, 2 Gy/day for 5 days) were sacrificed 24h post-irradiation. All IR exposures were limited to the lower abdomen area (1cm diameter), while the rest of the animal was protected by a specially designed cerrobend shield. EMSA analysis was used to examine the changes in NFκB DNA binding activity in the heart. Transcriptional activation of 88 mediators associated with NFκB signaling pathway was assessed using QPCR profiling. Phosphorylation of ERK1/2 and p38 that play a key role in NFκB signal transduction were examined using immunoblotting. Induced DNA fragmentation was measured using TdT nick end labeling. IR significantly induced NFκB DNA binding activity in the heart. Further more, real-time QPCR profiling showed a significant and differential modulation in the transcriptional responses of NFκB signaling pathway molecules. To that end, of the 88 genes analyzed, 28, 51 and 41 genes were upregulated after 2Gy, 10Gy and FIR, respectively. More importantly, at these exposures13 out of 28, 27 out of 51 and 25 out of 41 induced mediators of NFkB pathway were significantly upregulated. Conversely, lower abdominal IR exposure markedly suppressed 44, 20 and 30 genes after 2 Gy, 10Gy and FIR, respectively in the heart of the exposed animals. Compared to 2Gy, FIR significantly induced 26 genes, while 10Gy upregulated 27 genes. In addition, 6 and 15 genes were significantly upregulated after acute dose of 2 and 10Gy as opposed to fractionated dose. Consistently, immunoblotting analysis revealed a profound phosphorylation of both ERK1/2 and p38 in the heart. Interestingly, distant IR exposure significantly enhanced DNA fragmentation in the heart tissue. Taken together, these data clearly indicated an induced abscopal response in mice heart after clinically relevant doses of IR exposure. More importantly, these data implies that orchestration of NFκB signal transduction may play a key role in induced abscopal responses. Funding Support: Presbyterian Health Foundation, OKC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 486.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-486
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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