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:This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMGCR inhibitors, specifically simvastatin, are significantly associated with a reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several associated pathways. Higher levels of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and VLDL cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA. Meanwhile, RhoB is a key protein involved in the regulation of bladder cancer cell metastasis by simvastatin. Therefore, we tested the changes of key genes in bladder cancer cells after simvastatin (HMGCR inhibitor) treatment and overexpression of RhoB, respectively, using RNA sequencing.
2024-09-08 | GSE270394 | 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. Keywords: time-course, response to treatment
2006-12-31 | GSE4883 | GEO
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:Background Simvastatin modulates numerous stem cell functions, including stemness maintenance and differentiation. The present study aimed to explore the effect of simvastatin on the osteogenic differentiation of SCAPs in vitro. Methods Cells were isolated from apical papilla, and mesenchymal stem cell features were characterised. Cells were treated with various concentrations of simvastatin (100-1,000 nM). The mRNA expression profile of simvastatin-treated SCAPs was examined using RNA sequencing technique. The osteogenic differentiation abilities were assessed. Alkaline phosphatase activity was determined. The mineralisation was visualised using Alizarin Red S and Von Kossa staining. The osteogenic marker gene expression was determined using a quantitative polymerase chain reaction. Results RNA sequencing data demonstrated that simvastatin upregulated genes enriched in those pathways involving osteogenic differentiation, including the TGF-beta signalling pathway, FoxO signalling pathway, and MAPK signalling pathway, while the downregulated genes were involved in pathways related to cell proliferation and apoptosis, for example, DNA replication, cell cycle, and p53 signalling pathway. Simvastatin promoted mineral deposition in a dose-dependent manner, corresponding with the upregulation of osteogenic marker genes namely OSX, DMP1, DSPP, and OCN. Pretreatment with TGF-beta receptor inhibitor, SB431542, resulted in a moderately attenuated effect on simvastatin-induced mineralisation and osteogenic marker gene expression. Conclusions Simvastatin enhances osteogenic differentiation in SCAPs, potentially via TGF-beta signalling, implicating its potential role as an adjunctive molecule in dental pulp healing and regeneration in vital pulp treatment approaches.
2025-01-22 | GSE286540 | GEO
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:Effect of Simvastatin on endothelial cells
| PRJNA877683 | ENA
Project description:We report that simvastatin induces an immunoregulatory transcriptional profile in endothelial cells that is potent to modulate CD4+ T cell biology.
2021-10-28 | GSE171123 | 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:Microarray gene expression profiling reveals that simvastatin regulates the expression of M phase cell cycle genes and mevalonate metabolism
2023-05-01 | GSE215949 | GEO