Diclofenac inhibits esophageal squamous cell carcinoma through suppression of metabolic pathways and activation of p53 signaling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227127 | GEO | 2023/03/17
REPOSITORIES: GEO
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Project description:Transcriptional profiling of Esophageal Squamous Cell Carcinoma (ESCC) tumors comparing samples harbouring nuclear-stabilized p53 (NS+) versus unstable p53 (NS-) protein, determined through immunohistochemistry (IHC) staining of the tumor sections. The goal was to identify the genes that were differentially regulated between NS+ and NS- ESCC samples.
2024-03-29 | GSE218109 | GEO
Project description:BACKGROUND: As evidenced by epidemiological and etiological studies, the development of varicose veins is driven by risk-factors which support the development of venous hypertension and thus chronically augment circumferential stress of the venous wall (e.g. dysfunctional venous valves, pregnancy or obesity). We have previously verified the relevance of this biomechanical stimulus for the activation of venous endothelial as well as smooth muscle cells and the subsequent detrimental structural remodeling of the vein wall in experimental mouse models. METHODS: Here, transcriptome analyses revealed an increase in the expression of cyclooxygenase 2 (COX-2) in human venous endothelial cells upon exposure to biomechanical stress. Subsequently, we investigated the impact of diclofenac – a cyclooxygenase inhibitor – on responses of isolated mouse veins to augmented wall stress in vitro and on varicose-like venous remodeling in vivo. RESULTS: Diclofenac treatment decreased COX-2 protein abundance in mouse veins but had no significant impact on the expression of corresponding transcripts. Short-term exposure to elevated pressure levels stimulated the activity of matrix-metalloproteinase-2 (MMP-2) and mitogen activated protein kinases ERK1/2. Diclofenac decreased the level of activated MMP-2 and ERK1/2 in pressure-exposed mouse veins. Varikose-like remodeling of veins in the mouse auricle was significantly inhibited by transdermal application of diclofenac-containing phospholipid-micelles. This effect was associated with decreased COX-2 and MMP-2 abundance as well as cell proliferation. CONCLUSION: The cyclooxygenase inhibitor diclofenac interferes with short term activation of MAP-kinases and matrix-metalloproteinases in cells of the wall stress-exposed venous wall while attenuating venous remodeling in vivo. Thus, nonsteroidal anti-inflammatory drugs may be suitable to interfere with processes promoting the progression of varicose vein development and biomechanical activation of venous cells.
2021-01-12 | GSE121557 | GEO
Project description:The high recurrence rate and poor survival prospects of esophageal squamous cell carcinoma (ESCC) patients after treatment make the ongoing research on chemoprevention drugs for ESCC particularly important. In helping to solve this problem, we screened a large number of FDA-approved drugs and found that levodopa, a drug used to treat Parkinson’s disease, has an inhibitory effect on the growth of ESCC cells. To elucidate the molecular mechanisms, we applied mass spectrometry to investigate the anti-tumor activity of levodopa on ESCC. The results suggest that levodopa can down-regulate oxidative phosphorylation, non-alcoholic fatty liver disease (NAFLD) and parkinson disease pathways. SDHD, NDUFS4 and MT-CO3, major respiratory compounds in the mitochondria, were involved in these pathways. Down-regulation of these proteins is associated with mitochondrial dysfunction. Western blotting and immunofluorescence results confirmed the authenticity of proteomics data. Cell viability assay revealed that mitochondrial activity had been suppressed after levodopa treatment. Mitochondrial membrane potential reduction was detected by JC-1 and TMRE assays. And transmission electron microscope (TEM) analysis indicated that mitochondrial morphology changed. Taken together, levodopa inhibits the growth of ESCC through restraining the mitochondria.
2021-09-08 | PXD013824 | Pride
Project description:Esophageal squamous cell carcinoma (ESCC) is a heterogeneous cancer associated with high mortality rate. In India, it is the 6th most common cause of cancer-related mortality. In this study, we employed high-resolution mass spectrometry-based quantitative proteomics to characterize differential protein expression pattern associated with ESCC. We identified several differentially expressed proteins including PDPN, TOP2A, POSTN and MMP2 that were overexpressed in ESCC. In addition, we identified downregulation of esophagus tissue-enriched proteins such as SLURP1, PADI1, CSTA and small proline-rich proteins like SPRR3, SPRR2A, SPRR1A and CSTA, KRT4, KRT13 involved in squamous cell differentiation. We identified several overexpressed proteins belonging to 3q24-29 chromosomal region, corroborating CNV alterations in this region reported by several published studies. For example, we identified overexpression of SOX2, TP63, IGF2BP2 and RNF13 that are encoded by 3q26 region. Functional enrichment analysis revealed proteins involved in cell cycle pathways, DNA replication, spliceosome, and DNA repair pathways. We identified overexpression of multiple proteins that play a major role in alleviating ER stress. SYVN1/SEL1L complex forms the ER quality control machinery clearing misfolded proteins from ER. SYVN1 is an E3 ubiquitin ligase that ubiquitinates ER-resident proteins. There are also other non-canonical substrates of SYVN1 which are known to play a crucial role in tumor progression. Therefore, SYVN1 is a potential therapeutic target in ESCC.
2023-10-24 | PXD036238 | Pride
Project description:Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as model eukaryote to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. Especially pleiotropic drug resistance genes and genes under control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as well as zinc-responsive genes.
2011-05-17 | GSE29331 | GEO
Project description:Diclofenac is widely used as nonsteroidal anti-inflammatory drug leaving residues in the environment. To investigate effects on terrestrial ecosystems, we measured dissipation rate in soil and investigated ecotoxicological and transcriptome-wide responses in Folsomia candida. Exposure for 4 weeks to diclofenac reduced both survival and reproduction of F. candida in a dose-dependent manner. At concentrations ≥200 mg/kg soil diclofenac remained stable in the soil during a 21-day incubation period. Microarrays examined transcriptional changes at low and high diclofenac exposure concentrations. The results indicated that development and growth were severely hampered and immunity-related genes, mainly directed against bacteria and fungi, were significantly up-regulated. Furthermore, neural metabolic processes were significantly affected only at the high concentration. We conclude that diclofenac is toxic to non-target soil invertebrates, although its mode of action is different from the mammalian toxicity. The genetic markers proposed in this study may be promising early markers for diclofenac ecotoxicity.
2014-10-01 | GSE59589 | GEO
Project description:Our aim is to identify frequent genomic aberrations both in ESCC and esophageal dysplasia, and to discover important copy number-driving genes and microRNAs in ESCC. We carried out array-based comparative genomic hybridization (array CGH) on 59 ESCC resection samples and 16 dysplasia biopsy samples. Expression of genes at 11q13.3 was analyzed by real-time PCR and immunohistochemistry (IHC). Integrated analysis was performed to identify genes or microRNAs with copy number-expression correlations. Two group experiment, esophageal dysplasia vs. esophageal squamous cell carcinoma. Biological replicates: 16 dysplasias vs. 59 carcinomas
2013-04-29 | E-GEOD-46452 | biostudies-arrayexpress
Project description:We used microarrays to determine global gene expression in primary tumor tissues (ESCC) and matched normal tissues (adjacent normal esophageal mucosa) Paired primary ESCC tumor and normal tissues were compared (n=5).
2009-09-01 | E-GEOD-17351 | biostudies-arrayexpress
Project description:Gene expression analysis of diclofenac-treated rat cardiomyocytes vs non-treated rat cardiomyocytes. Goal of study is to identify changes on genes expression induced by diclofenac. The data analysis focused on genes that might be related to cardiotoxicity; genes expression ion channels and pathways.
2016-02-13 | GSE77880 | GEO
Project description:Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as model eukaryote to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. Especially pleiotropic drug resistance genes and genes under control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as well as zinc-responsive genes. Five independent yeast cultures were incubated with 100 µM diclofenac for 75 hours. Every 24h, cultures were diluted to OD600 ~0.1 in YNB containing 100 µM diclofenac. Five independent control cultures were grown in the absence of diclofenac.
2011-05-17 | E-GEOD-29331 | biostudies-arrayexpress