Simvastatin overcomes resistance to tyrosine kinase inhibitors in patient-derived, oncogene-driven lung adenocarcinoma models
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE249807 | GEO | 2023/12/12
REPOSITORIES: GEO
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Project description:HMG-CoA reductase inhibitors, statins, have beneficial vascular effects beyond their cholesterol-lowering action. These pleiotropic effects include an anti-inflammatory effect on macrophages. Since macrophages play a central role in atherogenesis, we further characterized the effects on peripheral blood monocyte-macrophages (HPBM). Using Affymetrix gene chip analysis of simvastatin-treated HPBM, we found that simvastatin treatment lead to the downregulation of the expression of many proinflammatory genes including several chemokines (e.g. MCP-1, MIP-1 alpha and β, RANTES, several other CC and CXC chemokines, IL-2 receptor-β, and leukemia inhibitory factor), members of the tumor necrosis factor family (e.g. lymphotoxin beta and TRAIL), VCAM-1, ICAM-3, and tissue factor (TF). Simvastatin also modulated the expression of several transcription factors essential for the inflammatory response: simvastatin downregulated the expression of NF-kappaB relA/p65 subunit and ets-1 transcription factor, and upregulated the expression of a novel atheroprotective transcription factor, Kruppel-like factor 2 (KLF-2). The effects of simvastatin on KLF-2 and its target genes were dependent on protein prenylation, since inhibitors of protein prenylation had a similar inhibitory effect in THP-1 derived macrophages. Additionally, by lentiviral overexpression KLF-2 we showed that the effect of simvastatin on MCP-1 and TF were dependent on KLF-2. We concluded that simvastatin had a strong anti-inflammatory effect on macrophages, which includes upregulation of the atheroprotective transcription factor KLF-2. These findings further explain the beneficial pleiotropic effects of statins on cardiovascular diseases. Keywords: time-course, response to treatment
2006-12-31 | GSE4883 | GEO
Project description:Toll-like receptor 2 (TLR2) is a pattern recognition receptor that, upon ligation by microbial molecules, interacts with other proteins to initiate pro-inflammatory responses by the cell. Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors), drugs widely prescribed to reduce hypercholesterolemia, are reported to have both pro- and anti-inflammatory effects upon cells. Some of these responses are presumed to be driven by effects on signaling proteins at the plasma membrane, but the underlying mechanisms remain obscure. We reasoned that profiling the effect of statins on the repertoire of TLR2-interacting proteins might provide novel insights into the mechanisms by which statins impact inflammation. In order to study the TLR2 interactome, we designed a co-immunoprecipitation (IP)-based cross-linking proteomics study. A hemagglutinin (HA)-tagged-TLR2 transfected HEK293 cell line was utilized to precipitate the TLR2 interactome upon cell exposure to the TLR2 agonist Pam3CSK4 and simvastatin, singly and in combination. To stabilize protein interactors, we utilized two different chemical cross-linkers with different spacer chain lengths. Proteomic analysis revealed important combinatorial effects of simvastatin and Pam3CSK4 on the TLR2 interactome. After stringent data filtering, we identified alpha-centractin (ACTR1A), an actin-related protein and subunit of the dynactin complex, as a potential interactor of TLR2. The interaction was validated using biochemical methods. RNA interference studies revealed an important role for ACTR1A in induction of pro-inflammatory cytokines. Taken together, we report that statins remodel the TLR2 interactome, and we identify ACTR1A, a part of the dynactin complex, as a novel regulator of TLR2-mediated immune signaling pathways.
2019-06-24 | PXD012759 | Pride
Project description:Statins reduce cardiovascular disease risk by lowering plasma low density lipoprotein (LDL)-cholesterol. To identify novel pathways that modulate statin response, we assessed the influence of simvastatin exposure on expression quantitative trait locus (eQTL) associations across the genome in 480 lymphoblastoid cell lines (LCLs). Cell lines were derived blood samples collected ant entry visit from participants in the Cholesterol and Pharmacogenomics (CAP) trial, who underwent a 6 week 40mg/day simvastatin trial. We identified 4590 cis-eQTLS that were independent of treatment status (FDR=1%) and six cis-eQTLS for which there was evidence of an interaction with treatment (FDR=20%). Genotypes and Phenotypes derived from these indivudals are available through dbGaP (Accession Number). eQTL results are available at: http://eqtl.uchicago.edu/cgi=bin/gbrowse/eqtl/ Dataset consists of 960 expression beadarrays (Illumina HumanRef-8v3) representing paired samples derived from 24-hour exposures of 480 lymphoblastoid cell lines (LCLs) to 2 micromolar simvastatin acid or control buffer.
2012-06-30 | E-GEOD-36868 | biostudies-arrayexpress
Project description:Statins reduce cardiovascular disease risk by lowering plasma low density lipoprotein (LDL)-cholesterol. To identify novel pathways that modulate statin response, we assessed the influence of simvastatin exposure on expression quantitative trait locus (eQTL) associations across the genome in 480 lymphoblastoid cell lines (LCLs). Cell lines were derived blood samples collected ant entry visit from participants in the Cholesterol and Pharmacogenomics (CAP) trial, who underwent a 6 week 40mg/day simvastatin trial. We identified 4590 cis-eQTLS that were independent of treatment status (FDR=1%) and six cis-eQTLS for which there was evidence of an interaction with treatment (FDR=20%). Genotypes and Phenotypes derived from these indivudals are available through dbGaP (Accession Number). eQTL results are available at: http://eqtl.uchicago.edu/cgi=bin/gbrowse/eqtl/
2012-07-01 | GSE36868 | GEO
Project description:HMG-CoA reductase inhibitors, statins, have beneficial vascular effects beyond their cholesterol-lowering action. These pleiotropic effects include an anti-inflammatory effect on macrophages. Since macrophages play a central role in atherogenesis, we further characterized the effects on peripheral blood monocyte-macrophages (HPBM). Using Affymetrix gene chip analysis of simvastatin-treated HPBM, we found that simvastatin treatment lead to the downregulation of the expression of many proinflammatory genes including several chemokines (e.g. MCP-1, MIP-1 alpha and β, RANTES, several other CC and CXC chemokines, IL-2 receptor-β, and leukemia inhibitory factor), members of the tumor necrosis factor family (e.g. lymphotoxin beta and TRAIL), VCAM-1, ICAM-3, and tissue factor (TF). Simvastatin also modulated the expression of several transcription factors essential for the inflammatory response: simvastatin downregulated the expression of NF-kappaB relA/p65 subunit and ets-1 transcription factor, and upregulated the expression of a novel atheroprotective transcription factor, Kruppel-like factor 2 (KLF-2). The effects of simvastatin on KLF-2 and its target genes were dependent on protein prenylation, since inhibitors of protein prenylation had a similar inhibitory effect in THP-1 derived macrophages. Additionally, by lentiviral overexpression KLF-2 we showed that the effect of simvastatin on MCP-1 and TF were dependent on KLF-2. We concluded that simvastatin had a strong anti-inflammatory effect on macrophages, which includes upregulation of the atheroprotective transcription factor KLF-2. These findings further explain the beneficial pleiotropic effects of statins on cardiovascular diseases. Experiment Overall Design: Cell culture studies. Experiment Overall Design: Human peripheral blood monocytes (HPBM) were isolated from buffy coats from healthy blood-donor volunteers (Finnish Red Cross, Helsinki, Finland) using Ficoll-Paque gradient centrifugation. None of the blood donors were on statin therapy. During isolation, monocytes from 3 individuals were pooled. Adherent cells were cultured in standard medium (20% human serum, Cambrex for differentiation into macrophages. The macrophage-phenotype at day 7 after isolation was confirmed with the typical shape of macrophages and also by macrophage-immunostaining (mAB CD68, DAKO, Denmark, dilution 1:200), where macrophages presented >95% of the cell population. The study protocol has been accepted by the Ethical Committee of the University of Kuopio. Experiment Overall Design: Simvastatin treatment. Experiment Overall Design: Simvastatin was a generous gift from Merck & Co. The inactive lactone form of simvastatin was hydrolyzed to the corresponding β-hydroxy acid. The HPBM-macrophages were treated with statin at day 7 after the isolation. 12 hours prior to statin treatment the cell growth media were changed to serum-free media. The statin-treated (10 uM simvastatin in serum-free media) cells were collected at 12 h and 24 h for Affymetrix analyses. The toxicity of simvastatin was assessed in cell culture: 5x concentration of simvastatin (50 uM) had no effect on cell viability. Experiment Overall Design: RNA isolation. Experiment Overall Design: Total RNA was isolated from the cells using Trizol reagent (Gibco BRL, USA) according to manufacturersâ?? instructions. The quality and amount of RNA was assessed by spectrophotometry (NanoDrop, USA) and by agarose gel electrophoresis. Experiment Overall Design: Microarray analyses. Experiment Overall Design: For Affymetrix analyses three separate HPBM cell isolation and simvastatin experiments were performed (HPBMs from 3 individuals at each time, total n=9). Cells were collected at 12 h and 24 h after the statin treatment. Total RNA was isolated as above. cDNAs were prepared from RNAs (5 ug of RNA) with reverse transcriptase (Superscript II primed by a poly (T) oligomer/T7 promoter). cDNAs were subsequently used as a template to make biotin-labeled cRNA with an in vitro transcription reaction. cRNAs (15 ug) were hybridized to Affymetrix HGU133 Plus 2.0 oligonucleotide arrays, which was processed and scanned according to manufacturerâ??s instructions. Each array quantifies the expression of over 47 000 transcripts (including full-length mRNA sequences and expressed sequence tags) derived from build 133 of the UniGene database (available at www.affymetrix.com). Experiment Overall Design: Microarray data analysis. Experiment Overall Design: Affymetrix GeneChip® Operating Software (GCOS) was used to generate .CEL files which were then converted into .DCP files using dChip (http://www.dchip.org) V1.3 software 28. The arrays were normalized to baseline array with median probe intensity, and gene expression data were generated calculating model-based expression values. In this study, genes were considered differentially expressed if they changed more than 1.5-fold (90% confidence bound of the fold change), absolute difference of signals was >100, at least 40% of the samples were called present in both groups and False Discovery Rate (FDR) was less than 1%. Hierarchical clustering was performed by dChip using Pearson correlation with a centroid-linkage method. Gene function analysis was performed by using the gene ontology mining tool GoSurfer incorporated in dChip program.
2008-06-13 | E-GEOD-4883 | biostudies-arrayexpress
Project description:The aim of our study was to assess the impact of simvastatin on the amount of cytosolic lipid droplets (LDs), which are implicated in many biological processes including proliferation, inflammation, carcinogenesis, apoptosis, necrosis or growth arrest. Human pancreatic cancer cells MiaPaCa-2 were treated with simvastatin (6 and 12 _M) for 24 hours. Changes in expression of genes related to lipid metabolism in the simvastatin-treated cells were examined by DNA microarray analysis. The treatment of the cells with simvastatin increased their intracellular content of LDs, partially due to the uptake of cholesterol and triacylglycerides from medium; but in particular, due to enhanced synthesis of triacylglycerides as proved by detection of significant overexpression of genes related to de novo synthesis of triacylglycerides and phospholipids. Further, simvastatin markedly influenced expression of genes directly affecting cell proliferation and signaling.
2013-11-21 | E-MTAB-1501 | biostudies-arrayexpress
Project description:Statins (HMG-CoA reductase inhibitors) are a widely used class of cholesterol-lowering drugs that have an established role in the medical management of cardiovascular disease. Their benefits have also been shown in the surgical setting with decreased cardiovascular complications and lower perioperative mortality following cardiac and vascular surgery. There is now considerable evidence showing statins have useful pleiotropic properties that extend beyond cholesterol lowering, including anti-inflammatory, anti-oxidant, immunomodulatory and fibrinolytic effects. Growing evidence suggests these effects may be useful in attenuating the proinflammatory and metabolic stress response to surgery and the benefit of statins may extend to other surgical settings such as abdominal surgery.
Laboratory studies demonstrate the surgically-relevant benefits of statins and show they decrease peritoneal inflammation, reduce the severity of intestinal ischaemia-reperfusion injury, improve survival in models of abdominal sepsis, decrease the formation of postoperative intraperitoneal adhesions and improve the healing of colonic anastomoses. Retrospective clinical studies show statins improve outcomes in sepsis, reduce the postoperative systemic inflammatory response syndrome (SIRS) and are associated with decreased rates of surgical wound infections and postoperative respiratory complications following various non-cardiac general surgical procedures. However, no prospective studies have specifically evaluated the perioperative use of statins in abdominal surgery. Using colorectal surgery as a model for major abdominal surgery, the investigators will conduct a randomised controlled trial evaluating the effect of perioperative statin use on postoperative morbidity, local and systemic inflammatory response, and functional recovery after surgery.
| 2079365 | ecrin-mdr-crc
Project description:Objective: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with metabolic syndrome (MetS) in humans and hepatic effects similar to non-alcoholic fatty liver disease through activation of the aryl hydrocarbon receptor (AHR) pathway. Dysregulation of cholesterol homeostasis, an aspect of MetS, is linked to NAFLD pathogenesis, and TCDD exposure is also linked to the suppression of genes that encode key cholesterol biosynthesis steps and changes in serum cholesterol levels. In a previous experiment, treating mice with TCDD in the presence of simvastatin, a 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) competitive inhibitor, increased toxicity in male mice, compared to TCDD alone. The aim of this study was to deduce a possible mechanism(s) for this increased liver injury. Methods: Male C57Bl/6 mice were treated with vehicle control or TCDD via oral gavage and were fed either standard or simvastatin-laced chow. Single nuclei RNA sequencing (snRNASeq) was performed in mouse liver to investigate the impact of treatment on distinct liver cell (sub)types that may explain differences in pathology between treatments. Results: We demonstrated that co-treated mice experienced exacerbated wasting and increased AHR activation compared to TCDD alone. Furthermore, relative proportions of cell (sub)types were different between TCDD alone and co-treated mice including important mediators of NAFLD progression such as hepatocytes and Kupffer cells. Co-treated mice promoted upregulation of lipid metabolism in hepatocytes, which is consistent with decreased fat accumulation seen in previous studies. Interestingly, the proportion of plasmacytoid dendritic cells (pDCs) increased in only co-treated mice, which may play an important role in the differences in immune cell infiltration between treatment groups. Conclusions: Our results suggest simvastatin co-treatment promotes a worse prognosis of TCDD-induced injury in mice and alterations in immune infiltration between treatments may influence liver injury severity.
2023-10-11 | GSE211018 | GEO
Project description:Based on the results from preclinical study, the investigators suggest that the addition of simvastatin at a dose of cardiovascular use (40 ~ 80 mg qd daily) may overcome cetuximab resistance in KRAS mutant colorectal cancer via B-Raf protein degradation and inducing Bim and Bad. Given the result of a phase II FOLFIRI plus cardiovascular dose of simvastatin (80mg qd daily) and this study, phase II study of conventional cetuximab treatment with 40 mg simvastatin is planned in metastatic colorectal cancer patients with KRAS mutation.
| 2101200 | ecrin-mdr-crc
Project description:Statins protect against the development of atherosclerosis via cholesterol-dependent and –independent mechanisms. Understanding the molecular mechanisms mediating simvastatin induced atheroprotective effects is critical for designing anti-atherosclerotic agents. Here, we showed that simvastatin decreases the expression of the Polycomb methyltransferase EZH2 in endothelial cells. To better understand the influence of the simvastatin-induced EZH2 downregulation on endothelial transcriptome, we performed RNA-sequencing study to evaluate differential gene expression after overexpression of EZH2 in the presence of simvastatin treatment. We found simvastatin treatment altered a subset of genes that can be rescued with EZH2 overexpression. Therefore, simvastatin treated endothelial cells display an atheroprotective phenotype by downregulating EZH2.
2017-08-18 | GSE85799 | GEO