Characterization of the transcriptional response to DNA in STING KO cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129436 | GEO | 2019/12/11
REPOSITORIES: GEO
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Project description:Purpose: Patients with advanced soft-tissue sarcomas (STSs) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional serine—threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining (NHEJ). Experimental design: To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacological inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen. Results: DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacological inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition. Conclusion: DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma
2023-09-25 | GSE243758 | GEO
Project description:Primary objectives: Effect of the highly potent CYP3A4 inhibitor ritonavir on the pharmacokinetics (PK) of erlotinib, measured as AUC0-24h, AUCmean, Cmax and Cmin
Primary endpoints: The effect of the highly potent CYP3A4 inhibitor ritonavir on the pharmacokinetics (PK) of erlotinib, measured as AUC0-24h, Cmax and Cmin.
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Project description:Viruses are obligate intracellular parasites that exploit the host metabolic machineries to meet their extraordinary biosynthetic demands. Integrative transcriptomic and lipidomic profiling confirmed that Middle East respiratory syndrome coronavirus (MERS-CoV) infection reprograms the host lipid metabolism. By exploring a bioactive lipid library, we identified a tool compound, AM580 which is highly potent in interrupting the life cycle of diverse viruses including MERS-CoV and influenza A virus.</br> Using click chemistry, the sterol regulatory element binding protein (SREBP) was identified as the primary cellular target of AM580 which accounts for its broad-spectrum antiviral activity. Mechanistic studies pinpoint multiple SREBP proteolytic processes and SREBP-regulated lipid biosynthesis pathways, including the downstream viral protein palmitoylation and double-membrane vesicles formation, that are indispensable for virus replication. Collectively, our study identifies a basic lipogenic transactivation event with broad relevance to human viral infections and represents SREBP as an ideal target for the development of broad-spectrum intervention strategies.
2018-11-26 | MTBLS762 | MetaboLights
Project description:Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. Existing therapies do not result in a functional cure in most individuals, necessitating new antiviral strategies against Hepatitis B virus (HBV). To identify additional therapeutic avenues, we performed a focused screen of epigenetic modifiers to identify inhibitors of HBV replication. From this work we identified small molecule inhibitors of the histone lysine demethylase 5 (KDM5) with antiviral activity against HBV. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) a prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as increased accumulation of the H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS 5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious. Together these data highlight discordance between the antiviral effects of GS 5801 observed in rodent livers.
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Project description:CID 70698683 is a novel broad-spectrum antiviral compound. To understand the broad-spectrum antiviral mechanism, the cellular gene expression changes by the treatment of CID70698683 was measured.
2015-11-25 | GSE72167 | GEO
Project description:Analysis of the transcriptional response of HEK293 or HEK293-STAT6 stable cell lines to poly(I:C) transfection. The hypothesis tested was that poly(I:C) transfection is capable of inducing the expression of STAT6-dependent antiviral genes. mRNA isolated from HEK293 or HEK293-STAT6 stable cell lines with control treatment or poly(I:C) transfection for 16 hours.
2011-11-21 | E-GEOD-26435 | biostudies-arrayexpress
Project description:Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. Existing therapies do not result in a functional cure in most individuals, necessitating new antiviral strategies against Hepatitis B virus (HBV). To identify additional therapeutic avenues, we performed a focused screen of epigenetic modifiers to identify inhibitors of HBV replication. From this work we identified small molecule inhibitors of the histone lysine demethylase 5 (KDM5) with antiviral activity against HBV. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) a prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as increased accumulation of the H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS 5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious. Together these data highlight discordance between the antiviral effects of GS 5801 observed in HBV-infected primary human hepatocytes.
2021-02-24 | GSE165727 | GEO
Project description:CID 70698683 is a novel broad-spectrum antiviral compound. To understand the broad-spectrum antiviral mechanism, the cellular gene expression changes by the treatment of CID70698683 was measured. HEp-2 cells grown in 6-well plates were treated with 5 microM of CID 70698683 for overnight and the cellular RNA was extracted (Treatment group). For control, DMSO was used instead of CID 70698683 (final concentration of 0.25%). Three replicates per group used.
2015-11-25 | E-GEOD-72167 | biostudies-arrayexpress
Project description:RNA sequencing of wild-type or Interferon Alpha receptor 1 Knockout MEF cells treated with DMSO or the Broad-spectrum Caspase Inhibitor Q-VD-OPh The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify of a mechanism by which mitochondria and downstream pro-apoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response, and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a pro-inflammatory type of cell death. To determine whether the pharmacological inhibition of caspases could recapitulate the phenotype caused by genetic deficiencies, we treated WT MEFs with broad-spectrum inhibitors of caspases (Q-VD-OPH). The inhibitor induced an increased expression of ISGs, similar to the effect of caspase or Apaf-1 deficiency. Next, we compared the transcriptional changes induced by caspase inhibition in WT and IFNAR1 KO cells, which lack a critical subunit of the receptor for IFNα/β (Muller et al., 1994). We observed that the absence of the IFNAR receptor abrogated the transcriptional response of the cells to caspase inhibition by Q-VD-OPH, demonstrating the role of type I IFNs in this response. RNA was extracted from duplicate samples and libraries generated for sequencing using the directional RNA-Seq library prep at the Yale Center for Genome Analysis. Libraries were sequenced using a Hiseq2500 sequencer to generate 76bp single-end reads. Duplicate samples were analyzed for each condition.
2014-12-03 | E-GEOD-63794 | biostudies-arrayexpress
Project description:Evaluation of the genome wide impact on gene expression of DNA-PK knockdown or enzymatic inhibition. DNA-PK expression is elevated in multiple tumor types. DNA-PK has recently been implicated in transcriptional regulation, so understanding genes modulated by DNA-PK may provide insight into disease progression 6 samples were analyzed. A genome-wide expression array was performed on a GeneChip Human Gene 2.0ST Array (Affymetrix, 902112) with C4-2 cells depleted of DNA-PK or treated with DNA-PK inhibitor for 24 hours
2015-07-13 | E-GEOD-63480 | biostudies-arrayexpress