Abstract Ascertaining the ionizing radiation (IR)-induced carcinogenesis through an abscopal effect would raise a paradigm shift in our understanding of the radiobiological effects and radiation carcinogenesis. EF24, a synthetic analog of curcumin with improved physicochemical properties has been shown to possess potent anticancer activity, both in vitro as well as in vivo. In this study, we investigated the oncogenic activation after IR in an organ (lung) distant from the exposure field. 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) with or without EF24 (i.p. 200μg/Kg, 3h prior to IR) treatment were sacrificed 1h through 2 weeks 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. DNA binding activity of AP-1, E2F1, cFOS and FRA1 were examined using EMSA analysis. Transcriptional activation of 88 oncogenes was assessed using QPCR profiling. Phosphorylation of CREB and JNK were examined using immunoblotting. Cellular localization of JunB, JunC and JunD were analyzed by immunohisto staining. IR significantly induced AP-1, E2F1, cFOS and FRA1 DNA binding activity in lungs distant from the exposure fields. EF24 completely and persistently (up to 2wks) suppressed IR-induced distant effect on AP-1, E2F1, cFOS and FRA1 DNA binding activity. Second, EF24 completely suppressed all 52, 31 and 64 oncogenes that were significantly upregulated after 2 Gy, 10Gy and 2Gyx5D exposures. We observed a similar inhibitory effect of oncogene transcriptome even after 2wk with EF24 treatment. Third, a profound increase in JunB, JunC and JunD levels observed in distant lung tissue after IR were significantly inhibited by EF24. Fourth, we observed a profound inhibition of IR-induced CREB phosphorylation with EF24 treatment in distant lungs. Taken together, these data clearly demonstrated an induced abscopal carcinogenic response in mice lungs after clinically relevant doses of IR exposure. The findings further imply that systemic administration of EF24 could potentially inhibit DNA binding activity, transactivation and translation of oncogenes and thereby mitigate IR-induced oncogenic activation at distant site. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2011-4203