DNA damage independent inhibition of NF-κB transcription by anthracyclines

Abstract

Transcriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-kB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-kB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-kB subunit RelA and its DNA binding sites, to limit NF-kB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF.We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immunemediated inflammatory diseases. The nuclear factor kappa B (NF-kB) family of transcription factors, comprising RelA, RelB, c-Rel, p100 and p105, plays a prominent role in regulating inflammation 2 . All members share the N-terminal REL-homology domain (RHD) responsible for IkB binding, nuclear localization, dimerization and DNA binding. On their C-terminal region, RelA, RelB and c-Rel contain a transactivation domain (TAD), responsible for their transcriptional activity 3 . While NF-kB activation is strictly required to trigger the inflammatory response, uncontrolled NF-kB activity can result in a failure to resolve inflammation, contributing to the establishment of a growing number of pathological conditions 4 . At steady state, transcriptionally active NF-kB family members, of which RelA is the most abundant, are retained in the cytoplasm by their interaction with inhibitors of kB (IkB) molecules. IkBa phosphorylation in response to a variety of stimuli leads to its proteosomal degradation, a step required for RelA nuclear localization, DNA binding and initiation of gene transcription 5 3 . RelA-dependent IkBa re-synthesis is essential for its nuclear eviction and the timely termination of NF-kB transcriptional activity 6 7 . Posttranslational modifications within both RHD and TAD add an additional layer of control over RelA-dependent gene transcription, activating or repressing its transcriptional activity by controlling RelA association with IkB, nuclear localization, interaction with transcriptional cofactors, D...

Suppression of JNK Pathway as a Novel Regulator of Chemo-Resistance in AML: A Meta-Analysis of Gene Signatures and Key Pathways

“…TLR family provides cyto-protective response after activation by recognizing exogenous ligands including various pathogen/microbial components (PAMPs; pathogen-associated molecular patterns) or endogenous ligands (DAMPs, damage-associated molecular patterns). Activation of TLR family lead to cell stress such as DNA damaging, reactive oxygen species (ROS), and heat shock proteins (Hsps) and has a considerable function in in ammatory response through downstream pathways nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB), AP-1, and p38 MAPK pathways 46,49 . Anthracyclines, as the immune-stimulatory chemotherapeutic agent, can promote TLRs-mediated immunogenic apoptotic cell death through increased emission of DAMPs by damaging DNA in tumor cells 50 . Based on our GSEA results, differential expression of several genes including PELI2 (Pellino2), RPS6KA2(RSK3), S100B, c-Jun, AKT3, and SPP1, may contribute to the aberrant signal transduction of TLRs upon TRIF/MyD88-mediated induction signaling in chemoresistance AML group.…”

“…Anthracyclines, as the immune-stimulatory chemotherapeutic agent, can promote TLRs-mediated immunogenic apoptotic cell death through increased emission of DAMPs by damaging DNA in tumor cells 50 . Based on our GSEA results, differential expression of several genes including PELI2 (Pellino2), RPS6KA2(RSK3), S100B, c-Jun, AKT3, and SPP1, may contribute to the aberrant signal transduction of TLRs upon TRIF/MyD88-mediated induction signaling in chemoresistance AML group.…”