The expression profile of cytochromes P450 (CYPs) and aldo-keto reductases (AKRs) in post-treatment breast carcinomas
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56259 | GEO | 2014/08/31
SECONDARY ACCESSION(S): PRJNA242772
REPOSITORIES: GEO
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Project description:Metabolism of anticancer drugs markedly affects their antitumor effects. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing taxanes and/or anthracyclines with therapy response and survival of breast carcinoma patients AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control non-neoplastic tissues after correction for multiple testing. Significant associations of CYP2B6 levels in tumors with expression of hormonal receptors were found. Significantly higher intratumoral levels of AKR1C1, AKR1C2, and CYP2W1 were found in responders to NACT compared with non-responders. Patients with high AKR1C2 and CYP3A4 levels had significantly longer disease-free survival than patients with low levels. Transcript levels of twenty-four selected human metabolic genes (CYPs and AKRs) were determined by qPCR in post-treatment tumor and non-neoplastic tissue samples from 68 breast carcinoma patients treated by anthracycline and/or taxane based neoadjuvant chemotherapy. EIF2B1, MRPL19, IPO8, and UBB were used as reference genes for data normalization.
2014-08-31 | E-GEOD-56259 | biostudies-arrayexpress
Project description:Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs) lack CYP2C19 metabolic capacity. Thus, unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 PMs. However, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 PMs because there is currently no model for this phenotype. Here, using human iPS cells and our highly efficient genome editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells (CYP2C19-KO HLCs) as a novel CYP2C19 PM model for drug development and research. The gene expression levels of hepatocyte markers were similar between WT HLCs and CYP2C19-KO HLCs, suggesting that CYP2C19 deficiency did not affect the hepatic differentiation potency. We also examined CYP2C19 metabolic activity by measuring S-mephenytoin metabolites using LC-MS. The CYP2C19 metabolic activity was almost eliminated by CYP2C19 knockout. Additionally, we evaluated whether clopidogrel (CYP2C19 substrate)-induced liver toxicity could be predicted using our model. Unexpectedly, there was no significant difference in cell viability between clopidogrel-treated WT HLCs and CYP2C19-KO HLCs. However, the cell viability in clopidogrel- and ketoconazole (CYP3A4 inhibitor)-treated CYP2C19-KO HLCs was significantly enhanced as compared with that in clopidogrel- and DMSO-treated CYP2C19-KO HLCs. This result suggests that CYP2C19-KO HLCs can predict the clopidogrel-induced liver toxicity. We succeeded in generating CYP2C19 PM model cells using human iPS cells and genome editing technologies for pharmaceutical research.
2019-05-07 | GSE123937 | GEO
Project description:The aim of this study was to quantify enzymes and transporters in 20 human kidney cortex fractions. Using targeted accurate mass retention time (AMRT) and global proteomic approaches, 6 UGTs, 3 CYPs, 22 transporters, 1 adhesion and 1 plasma membrane marker were quantified; Eight of these proteins were identified for the first time in the kidney. The global proteomic method identified >4000 proteins. Kidney CYP2B6, CYP3A5 and CYP4F2 showed generally low expression.
2021-08-30 | PXD020996 | Pride
Project description:Orally administered drugs are absorbed and metabolized in the intestine. In order to accurately predict pharmacokinetics in the intestine, it is essential to understand the intestinal expression profiles of genes related to drug absorption, distribution, metabolism, and excretion (ADME). However, in many previous studies, gene expression analysis in the intestine has been carried out using specimens from cancer patients. In this study, in order to obtain a more accurate gene expression profile, biopsy samples were collected from 14 patients under endoscopic observation and RNA-seq analysis was performed. Gene expression analysis of drug metabolizing enzymes (CYPs), non-CYP enzymes, nuclear receptors, drug conjugating enzymes (UGTs and SULTs), and apical and basolateral drug transporters was performed in biopsy samples from the duodenum, ileum, colon, and rectum. The proportions of the CYPs expressed in the ileum were 25% (CYP3A4), 19% (CYP2C18), and 14% (CYP3A5). CYP3A4 and CYP2C19 were highly expressed in the duodenum and ileum, but not in the colon and rectum. In the ileum, apical transporters such as P-gp, PEPT1, BCRP, MRP2, and ASBT were strongly expressed, and the expression levels of P-gp and ASBT in the ileum were higher than those in other regions. In the ileum, basolateral transporters such as OSTα, OSTβ, and MRP3 were strongly expressed. Furthermore, we identified specific markers for the duodenum, ileum, colon, and rectum by conducting comprehensive gene expression analysis. We succeeded in obtaining gene expression profiles of drug ADME-related genes in vivo human intestinal epithelial cells. We expect that this information would be useful for accurate prediction of the pharmacokinetics of oral drugs.
2021-04-30 | GSE156453 | GEO
Project description:AKR1C1, a member of the AKR1C family, has been identified as a key player in cancer progression, promoting cancer cell proliferation and inhibiting apoptosis. Here, we identified AKR1C1 as a potential crucial gene significantly associated with oxaliplatin (OXA) sensitivity and unfavorable clinical outcomes through the transcriptome analysis of OXA-sensitive and -resistant colorectal cancer cell lines. Both in vitro and in vivo, AKR1C1 promotes cancer cell proliferation and confers OXA chemoresistance in colorectal cancer cells. Mechanistically, AKR1C1 interacts with and activates STAT3 and increases glutathione (GSH) levels, resulting in chemoresistance in colorectal cancer cells. Moreover, pharmacologic inhibition of AKR1C1 with alantolactone restores the sensitivity of resistant cell lines to OXA and the combined treatment of alantolactone with OXA exhibits superior antitumor effects in mouse xenografts. Collectively, the present study offers compelling evidence that AKR1C1 expression confers resistance to OXA in colorectal cancer, providing a promising strategy to circumvent chemoresistance.
2024-12-11 | GSE235026 | GEO
Project description:The cytochrome P450 3As (CYP3As) are abundantly expressed in the liver and metabolize many commonly prescribed medications. Their expression is highly variable between individuals with little known genetic cause. Despite extensive investigation, cis-acting genetic elements that control the expression of CYP3As remain uncharacterized. Using chromatin conformation capture (4C assays), we detected reciprocal interaction between a distal regulatory region (DDR) and the CYP3A4 promoter. The DRR colocalizes with a variety of enhancer marks and was found to promote transcription in reporter assays. CRISPR-mediated knockout of the DRR decreased expression of CYP3A4, CYP3A5, and CYP3A7, supporting its role as a shared enhancer regulating the expression of three CYP3A genes. Here we provided data generated from ATAC-Seq analysis of human primary hepatocytes originating from both black and white donors.
2023-06-26 | GSE207590 | GEO
Project description:The cytochrome P450 3As (CYP3As) are abundantly expressed in the liver and metabolize many commonly prescribed medications. Their expression is highly variable between individuals with little known genetic cause. Despite extensive investigation, cis-acting genetic elements that control the expression of CYP3As remain uncharacterized. Using chromatin conformation capture (4C assays), we detected reciprocal interaction between a distal regulatory region (DDR) and the CYP3A4 promoter. The DRR colocalizes with a variety of enhancer marks and was found to promote transcription in reporter assays. CRISPR-mediated knockout of the DRR decreased expression of CYP3A4, CYP3A5, and CYP3A7, supporting its role as a shared enhancer regulating the expression of three CYP3A genes. Here we provided data generated from circular chromatin confirmation capture followed by sequencing (4C-Seq) analysis of human primary hepatocytes originating from both black and white donors.
2023-06-26 | GSE207790 | GEO
Project description:The abstract of the associated publication (Selga E, Noé V, Ciudad CJ. Biochemical Pharmacology 2007 Sep 8; Article in press) is the following:; While studying differentially expressed genes between sensitive and 10-5 M Methotrexate (MTX) resistant HT29 human colon cancer cells, we identified some members of the aldo-keto reductase (AKR) superfamily. The study was followed with the member AKR1C1 (EC 1.1.1.213), validating its increase in mRNA and protein levels in MTX resistant cells. The genomic content for AKR1C1 remained unchanged between sensitive and resistant cells, thereby excluding a mechanism of AKR1C1 gene amplification. Thus, we cloned the AKR1C1 human promoter and performed luciferase experiments that revealed a transcriptional regulation of the gene in the resistant cells. Computational studies showed a putative binding site for the transcription factor Sp1. The co-transfection of Sp1 or Sp3 with different constructs of AKR1C1 promoter deletions, including and excluding the proximal GC-box, demonstrated a key role for these factors in regulating AKR1C1 transcriptional activity. Gel-shift assays revealed an increase in Sp1 and Sp3 binding in resistant compared to sensitive cells, without differences in Sp1 protein levels. Dephosphorylation of the extracts coincided with a decrease in Sp1 binding, which is consistent with a process of regulation of Sp1 by phosphorylation. We also investigated the possible relationship between AKR1C1 expression and MTX action. Overexpression of AKR1C1 counteracted the S-phase accumulation of cells and apoptosis caused by MTX treatment. This suggests a role of AKR1C1 in cell proliferation. Finally, overexpression of AKR1C1 in MTX sensitive HT29 cells conferred resistance to the chemotherapeutic agent and silencing of AKR1C1 by means of iRNA technology sensitized the cells to MTX. Experiment Overall Design: Two cell lines are compared in the study, which are HT29 colon cancer cells sensitive to methotrexate and HT29 cells resistant to 10e-5M methotrexate. Six samples are provided, which correspond to triplicates of each cell line. The samples provided were subsequently normalyzed and analyzed using the specific software GeneSpring GX 7.3.1
2008-06-16 | E-GEOD-9412 | biostudies-arrayexpress
Project description:The RNA-seq revealed that only 35 genes (with padj<0.05) were differentially expressed after the OMD 10 ng/ml treatment, and with relatively modest fold-changes to expression. GSEA analysis using webgestalt on GO terms revealed an increase of some genes linked to the response to acid chemicals (genes AKR1C1, AKR1C2, AKR1C3) and a decrease of few genes involved extracellular structure organization (GO:0043062) and ossification (genes ACAN and IBSP), and of the molecular function of actin binding. The Reactome database revealed an up-regulation of genes responsible of collagen network degradation and a down-regulation of ECM proteoglycans, ECM organization, collagen formation, and integrin cell-surface interactions.
2023-04-26 | GSE230198 | GEO
Project description:The abstract of the associated publication (Selga E, Noé V, Ciudad CJ. Biochemical Pharmacology, 2008) is the following: While studying differentially expressed genes between sensitive and 10-5 M Methotrexate (MTX) resistant HT29 human colon cancer cells, we identified some members of the aldo-keto reductase (AKR) superfamily. The study was followed with the member AKR1C1 (EC 1.1.1.213), validating its increase in mRNA and protein levels in MTX resistant cells. The genomic content for AKR1C1 remained unchanged between sensitive and resistant cells, thereby excluding a mechanism of AKR1C1 gene amplification. Thus, we cloned the AKR1C1 human promoter and performed luciferase experiments that revealed a transcriptional regulation of the gene in the resistant cells. Computational studies showed a putative binding site for the transcription factor Sp1. The co-transfection of Sp1 or Sp3 with different constructs of AKR1C1 promoter deletions, including and excluding the proximal GC-box, demonstrated a key role for these factors in regulating AKR1C1 transcriptional activity. Gel-shift assays revealed an increase in Sp1 and Sp3 binding in resistant compared to sensitive cells, without differences in Sp1 protein levels. Dephosphorylation of the extracts coincided with a decrease in Sp1 binding, which is consistent with a process of regulation of Sp1 by phosphorylation. We also investigated the possible relationship between AKR1C1 expression and MTX action. Overexpression of AKR1C1 counteracted the S-phase accumulation of cells and apoptosis caused by MTX treatment. This suggests a role of AKR1C1 in cell proliferation. Finally, overexpression of AKR1C1 in MTX sensitive HT29 cells conferred resistance to the chemotherapeutic agent and silencing of AKR1C1 by means of iRNA technology sensitized the cells to MTX. Keywords: DHFR, Methotrexate, drug-resistance
2007-12-30 | GSE9412 | GEO