The effect of PLK1 inhibitor BI6727 on transcriptomic profile of Transforming Growth Factor β 1 (TGFB1) -mediated gene expression in mouse myofibroblast
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ABSTRACT:
PROVIDER: PRJNA598163 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10804475_1.fastq.gz | Fastqsanger.gz | |||
| SRR10804475_2.fastq.gz | Fastqsanger.gz | |||
| SRR10804476_1.fastq.gz | Fastqsanger.gz | |||
| SRR10804476_2.fastq.gz | Fastqsanger.gz | |||
| SRR10804477_1.fastq.gz | Fastqsanger.gz |
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Project description:To determine the underlying mechanisms of PLK1 inhibitor BI6727 alleviating TGFB1-induced the differentiation of myofibroblast, we performed RNA-seq to define the global gene expression of embryonic mouse fibroblast (NIH/3T3 cell line) that treated with BI6727 or vehicle (DMSO) with or without TGFB1 stimulation.
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Project description:Polo-Like Kinase 1 (PLK1), a serine/threonine kinase involved in cell cycle regulation at the G2/M transition, is associated with high-risk neuroblastoma (NB) and unfavorable patient outcome. Recently, we and others demonstrated that PLK1 is a potential drug target in neuroblastoma and reported antitumoral actvity of the PLK1 inhibitor BI2536 in preclinical models of NB. We here analyzed the effects of the ATP-competitive PLK1 inhibitor GSK461364 on typical tumorigenic properties of preclinical in vitro and in vivo models of NB. Treatment of NB cells with GSK461364 resulted in decreased cell viability and reduction of proliferative capacity, and led to cell cycle arrest and massive induction of apoptosis. These phenotypic consequences were observed at low-dose nanomolar levels and were independent of the MYCN copy number status of the cell lines. In vivo treatment with GSK461364 led to a strong delay in tumor development and to a highly significant increase in survival in the treatment group. These preclinical findings highlight the promise of PLK1 inhibitors as novel agents for NB and serve as rationale to move forward with early phase clinical trials in children.
2015-03-21 | GSE67102 | GEO
Project description:Pericryptal myofibroblasts in the colon and rectum play an important role in regulating the normal colorectal stem cell niche and facilitating tumour progression. Myofibroblasts have previously mostly been distinguished from normal fibroblasts only by the expression of α smooth muscle actin (αSMA). We now identify AOC3, a surface monoamine oxidase, as a new marker of myofibroblasts by showing that it is the target protein of the myofibroblast reacting monoclonal antibody (mAb), PR2D3. The normal and tumour tissue distribution and the cell line reactivity of AOC3 match that expected for myofibroblasts. We have shown that the surface expression of AOC3 is sensitive to digestion by trypsin and collagenase and that anti-AOC3 antibodies can be used for FACS sorting of myofibroblasts obtained by non-enzymatic procedures. Whole genome microarray mRNA expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly expressed differentially between these two cell types; NKX2-3 and LRRC17 are expressed in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts. Transforming Growth Factor β (TGFβ) substantially down-regulated AOC3 expression in myofibroblasts but not in skin fibroblasts, in which it dramatically increased the expression of αSMA. A knockdown of NKX2-3 in myofibroblasts caused a decrease of myofibroblast-related gene expression and an increased expression of the fibroblast associated gene, SHOX2, suggesting that NKX2-3 is a key mediator for maintaining myofibroblast characteristics. Our results show that colorectal myofibroblasts, as defined by the expression of AOC3, NKX2-3 and other markers, are a distinctly different cell type from TGFβ activated fibroblasts. colorectal myofibroblast specific markers and expression profiles were sought by comparing four primary myofibroblast cultures to a panel of four dermal and foreskin fibroblast cell lines Four primary myofibroblast cultures established from adult human colon compared to four skin fibroblast cell lines to identify intestinal myofibroblast specific markers
2016-04-06 | E-GEOD-77474 | biostudies-arrayexpress
Project description:Targeting of the YAP/SMAD molecular circuit inhibits a TGFb1-induced myofibroblast phenotype
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Project description:Analysis of MCF7 breast cancer cells treated with estadiol for 6 h in presence or absence of the specific PLK1 inhibitor BI2536. Together with CHIP and global phosphoproteome data, the results demonstrate a key role of PLK1 in the estrogen receptor-mediated gene response. Hormone-deprived MCF7 cells were pretreated with BI2536 or vehicle (DMSO) followed by induction with estradiol (E2) or vehicle (ethanol). RNA of each condition was analysed in triplicate on an Agilent Human genome 4x44k v2 microarray [note: MCF7_DMSO_E2_rep3 sample was a clear technical outlier (poor hybridization), and was therefore excluded from the further analysis/this record].
2014-01-01 | E-GEOD-46856 | biostudies-arrayexpress
Project description:Transcription profiling by microarray was performed to pinpoint the roles of transforming growth factor B1 (TGFB1) in embryonic differentiation of the small intestine. An organ culture system in which mouse jejunal rudiments were placed on semipermeable platforms and fed with chemically defined serum-free media, supplemented with two concentrations of TGFB1.
2017-04-03 | E-MTAB-4509 | biostudies-arrayexpress
Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance. Gene expression profiling of Human Embryonic Kidney Cells (HEK-TERV) under different conditions: PMN, PDK1, MYC and E545K
2013-07-31 | E-GEOD-30669 | biostudies-arrayexpress
Project description:Analysis of MCF7 breast cancer cells treated with estadiol for 6 h in presence or absence of the specific PLK1 inhibitor BI2536. Together with CHIP and global phosphoproteome data, the results demonstrate a key role of PLK1 in the estrogen receptor-mediated gene response.
2014-01-01 | GSE46856 | GEO
Project description:Fibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc's role in FLC tumor growth remains enigmatic. Employing an unbiased systems-based approach, we uncovered a new role of DNAJ-PKAc oncoprotein in FLC and identified downstream kinases involved in this process. Functional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc's centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumor growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues. Our findings underscore the role of DNAJ-PKAc in rewiring signaling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.
2023-12-19 | GSE250059 | GEO
Project description:Background: Mechanistic target of rapamycin (mTOR) is a nodal serine/threonine protein kinase critical for the control of fundamental cellular processes. Dysregulated mTOR signalling has been shown in cancer, COPD and idiopathic pulmonary fibrosis (IPF). mTOR forms the catalytic subunit of 2 protein complexes: mTORC1 and mTORC2 which differ in upstream inputs, downstream effects and sensitivity to the allosteric inhibitor rapamycin. Aim: To compare the effects of the mTORC1 inhibitor rapamycin with an ATP-competitive inhibitor of mTORC1/2, AZD8055, on TGFβ1 induced transcriptional responses during myofibroblast differentiation by RNA-Seq analysis. Methods: Primary human lung fibroblasts were treated with TGFβ1 for 24h to induce myofibroblast differentiation and extra cellular matrix (ECM) production in the presence of rapamycin or AZD8055. Fibroblasts were also treated with rapamycin or AZD8055 without TGFβ1. Total mRNA was analysed by RNA-Seq. Results: On a global transcriptomic level, TGFβ1 significantly affected the expression of ~4,200 genes by more than 1.5 fold, of which ~1,100 changes were reversed by pan-mTORC1/2 inhibition, while being insensitive to rapamycin. Only 15 gene changes were reversed exclusively by rapamycin. Analysis of the rapamycin-insensitive, mTOR sensitive myofibroblast transcriptome revealed ECM-receptor interaction, metabolism and actin cytoskeleton regulation as major affected pathways. Conclusions: Our data support the conclusion that therapeutic approaches aimed at interfering with TGFb1 induced myofibroblast differentiation and ECM production require dual mTOR1/2 inhibition and may, in part, explain the lack of clinical efficacy of everolimus in the context of IPF.
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