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Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-?B p65-Regulated Gene Expression.

ABSTRACT: Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II through the transcribed gene, we tested the effects of camptothecin and of the approved TOP1 inhibitors Topotecan and SN-38 on TNF?-induced gene expression. RNA-seq experiments showed that inhibition of TOP1 but not of TOP2 activity suppressed the vast majority of TNF?-triggered genes. The TOP1 effects were fully reversible and preferentially affected long genes. TNF? stimulation led to inducible recruitment of TOP1 to the gene body of IL8, where its inhibition by camptothecin reduced transcription elongation and also led to altered histone H3 acetylation. Together, these data show that TOP1 inhibitors potently suppress expression of proinflammatory cytokines, a feature that may contribute to the increased infection risk occurring in tumor patients treated with these agents. On the other hand, TOP1 inhibitors could also be considered as a therapeutic option in order to interfere with exaggerated cytokine expression seen in several inflammatory diseases.

SUBMITTER: Riedlinger T

PROVIDER: S-EPMC6627772 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression.

Riedlinger Tabea T Bartkuhn Marek M Zimmermann Tobias T Hake Sandra B SB Nist Andrea A Stiewe Thorsten T Kracht Michael M Schmitz M Lienhard ML

Cancers 20190625 6

Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II through the transcribed gene, we tested the effects of camptothecin and of the approved TOP1 inhibitors Topotecan and SN-38 on TNFα-induced gene expression. RNA-seq experiments showed that inhibition of ...[more]

PMID: 31242600

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Project description:BackgroundThe NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-κB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins targeting the NF-κB pathway to mitigate the anti-viral effects of NF-κB-dependent host immunity.ResultsIn this study we have demonstrated using a variety of assays, in a number of different cell types including primary cells, that plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx is a broad antagonist of NF-κB signalling active against diverse innate NF-κB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-κB transcription factor p65, but not NF-κB family members p50 or p100, preventing nuclear translocation of p65. We found that broad antagonism of NF-κB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity.ConclusionsWe have discovered a novel mechanism by which lentiviruses antagonise NF-κB activation by targeting p65. These findings extend our knowledge of how lentiviruses manipulate universal regulators of immunity to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists. Importantly our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of NF-κB.

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Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-?B p65-Regulated Gene Expression.

Publications

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression.

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