PO-158 Induction of interferon signalling by natural DNA-binding compounds with cancer preventive activity

Abstract

IntroductionCancer preventive activity of natural DNA-binding compounds (Curcumin, Quercetin, Resveratrol, Genistein, Fisetin, Coumarin, Apigenin, EGCG, Thymoquinon and Naringenin) is considered to be realised via influence on different signalling pathways including NF-kappaB inhibition and p53 activation. In our previous studies we demonstrated that minor groove binding ligands prevent PARP1 interaction with DNA and by this way activate retrotransposon expression. Taking into consideration that many natural DNA-binding compounds could interact with DNA helix minor groove, we propose that this mechanism may be also realised by these compounds. As interferon (INF) signalling is induced by retrotransposon expression, its enhancement may be observed in cells treated with natural DNA-binding compounds.Material and methodsTo analyse influence of natural DNA-binding compounds on INF-signalling, we employed a reporter assay that detected an IFN response through the activation of a consensus IFN-sensitive response element (ISRE), which drove the expression of mCherry. We performed flow cytometry using cell line with ISRE-mCherry reporter after the cell treatment with non-toxic dose of the compounds. Obtained data were analysed by WinList 3D program. Curaxin, a new prospective drug with anticancer and tumour preventive activity, was used as a positive control, as previously its effect on the INF-signalling was demonstrated.Results and discussionsWe found that a whole number of natural DNA-binding compounds cause a significant enhancement in INF-signalling activity. In particular, treatment of cells with Curcumin, Genistein, Kaempferol and Sangvinarin led to increase in the proportion of cells expressing mCherry under the control of an INF-sensitive promoter in 3.5, 2.4, 4.8, 2.3, and 1.8 times, respectively. Coumarin, Thymoquinon, Quercetin и Apigenin positive influence on INF signalling was also observed, although, it was not significant. It should be noted that activation of INF-signalling was observed at the same concentrations of natural DNA-binding compounds, which caused histone H1 relocalization to nuclei.ConclusionThus, we demonstrated that additionally to NF-kappaB inhibition and p53 activation (already described mechanisms for the anticarcinogenic action of phytonutrients) the activation of INF-signalling can be an additional mechanism by which the DNA-binding compounds induce both anticarcinogenic and tumour preventive effects.This study was supported by Russian Science Foundation (17–15–01526).