Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CDK7 inhibition by LDC4297 in Mia-Paca2 and Panc89 cells

ABSTRACT: Inhibition of the dual function cell cycle and transcription kinase CDK7 is known to affect the viability of cancer cells, but the mechanisms underlying cell line-specific growth control remain poorly understood. Here, we employed a previously developed, highly specific small molecule inhibitor that non-covalently blocks ATP binding to CDK7 (LDC4297) to study the mechanisms underlying cell line-specific growth using a panel of genetically heterogeneous human pancre-atic tumor lines as model system. Although LDC4297 diminished both transcription rates and CDK T-loop phosphorylation in a comparable manner, some PDAC lines displayed significantly higher sensitivity than others. We focused our analyses on two well-responsive lines (Mia-Paca2 and Panc89) that, however, showed significant differences in their viability response to extended exposure to limiting LDC4297 concentrations. Biochemical and RNAseq analysis revealed strik-ing differences in gene expression and cell cycle control. Especially the downregulation of a group of cell cycle control genes, among them CDK1/2 and CDC25A/C, correlated well to the observed viability differences in Panc89 versus Mia-Paca2 cells. A parallel downregulation of regulatory pathways supported the hypothesis of a feedforward programmatic effect of CDK7 inhibitors, eventually causing hypersensitivity of PDAC lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193737 | GEO | 2022/01/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Exosomes and cells protein content from human subpopulations of pancreatic ductal adenocarcinoma (PDAC)

Project description:Characterization of the protein composition of exosomes and subpopulations of cells from four human PDAC cell lines (BxPC-3, PANC-1, T3M4, and MIA PaCa-2), via liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI–MS/MS).

2022-01-25 | PXD023529 | Pride

Apoptosis-associated speck-like protein containing a CARD regulates the growth of pancreatic ductal adenocarcinoma

Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes but also a proapoptotic molecule. We clarified the role and mechanisms of ASC in vitro data based on PDAC cells. ASC expression in PDAC cells was downregulated using small-interfering (si)RNA, and gene expression was assessed by RNA sequencing. PDAC cells were further analyzed using a proliferation assay and cell cycle analysis. We observed high ASC expression in multiple PDAC cells, and downregulation of ASC resulted in inhibition of PDAC cell growth and altered expression of cell cycle-related genes. Downregulation of ASC inhibited tumor progression by modulating the cell cycle in PDAC cells.

2021-11-18 | GSE168842 | GEO

Gene expression profiles of BxPC-3, MiaPaCa-2 and PANC-1 cell lines treated with DMSO and THZ1 respectively

Project description:By screening an epigenetic-related compound library, we identified THZ1, a covalent inhibitor of CDK7, as a promising candidate. Multiple long-established and patient-derived PDAC cell lines (PDC) were used to validate the efficacy of THZ1 in vitro. In addition, patient-derived xenograft (PDX) models and animal models of PDAC were utilized for examining THZ1 efficacy in vivo. Furthermore, RNA-Seq and H3K27Ac-based Super-Enhancers (SEs) analyses were performed to reveal the molecular mechanism of THZ1 treatment. Lastly, PDAC cell lines with primary or acquired resistance to THZ1 were investigated to explore the potential mechanism of THZ1 susceptibility.

2019-02-01 | GSE121273 | GEO

Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells

Project description:This microarray is an analysis of differentially expressed genes in three pancreatic ductal adenocarcinoma cell lines treated with LXR-agonist GW 3965. We first report that GW 3965 has antiproliferative effects in three PDAC cell lines. This microarray was designed to identify key mechanisms of the antiproliferative effect of LXR agonists within pancreatic cancer cell lines. Total RNA obtained from BxPC-3, MIA-PaCa-2, and PANC-1 pancreatic cancer cells grown in culture treated GW 3965 or ethanol (vehicle control) for 72 hours.

2014-04-15 | E-GEOD-51656 | biostudies-arrayexpress

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_24Hr_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172443 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Sensitive_MM_Cell_Lines_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Sensitive MM cell lines (H929 and MM1S; 24 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172444 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_6Hr_RNA-seq]

2022-04-01 | GSE172442 | GEO

miRNA signatures underly chemoresistance in the gemcitabine-resistant pancreatic ductal adenocarcinoma cell line MIA PaCa-2 GR

Project description:Chemotherapy resistance is a major clinical issue for pancreatic adenocarcinoma (PDAC). MicroRNAs (miRNAs) play an important role in cancer progression and chemoresistance. In this study, we addressed the association between miRNA expression profiles and gemcitabine (Gem) resistance. A Gem sensitive (GS) PDAC cancer cell line, MIA PaCa-2, and its Gem resistant (GR) progeny MIA PaCa-2 GR, was used to determine miRNA expression changes by resistance to Gemcitabine. miRNA-seq was used to determine the miRNA expression profiles in these cell lines. Ingenuity Pathway Analysis (IPA) was performed to determine the biological functions of differentially expressed miRNAs. In total, 1867 miRNAs were detected in the two cell lines. We found that the miRNA expression profiles were different between the GR and its sensitive isogenic parental GS cell line, and certain differentially expressed miRNAs were only detected in one or the other of these PDAC cell lines. A total of 97 (5.2%) miRNAs were significantly differentially expressed between GR and the GS cell lines, of which 65 (3.5%) miRNAs were upregulated and 32 (1.7%) miRNAs were downregulated. The miRNAs with the most significant differential expression in the GR cell line as compared with GS were primarily involved in the following biological processes: cell proliferation, cell migration & invasion, chemo-sensitization, alternative splicing, apoptosis, and angiogenesis. These miRNAs from cell lines were further refined to a subset and were analyzed in patient samples where expression was used to identify patients with recurrent tumors. Taken together, the results suggest that these miRNAs may play important roles in Gem resistance in PDAC. This study’s findings provides a basis for further research in the diagnosis and treatment selection for PDACs with gemcitabine resistance.

2024-07-01 | GSE269190 | GEO

Paricalcitol and hydroxychloroquine modulates extracellular matrix and enhance chemotherapy efficacy in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and limited therapeutic options. In a previous publication, our group defined some of the mechanisms that vitamin D analogue paricalcitol (P) and hydroxychloroquine (H) potentiated the effects of gemcitabine-based chemotherapy in PDAC. Based on this, we hypothesized that the mechanisms of potentiation of 5-Fluorouracil (5FU) and oxaliplatin-based chemotherapy by PH may include different pathways than what was seen with gemcitabine-based therapy. Using MIA PaCa-2, HPAC and KPC cell lines, the combination of PH significantly increased the cell death, apoptosis, and S-phase cell cycle arrest. In vivo, the combination therapy inhibited PDAC growth and altered the immune landscape by activating T and NK cells. Proteomic analysis revealed that, significant reduction in ECM proteins, specifically integrin beta-4 (ITGB4) which was also seen with gemcitabine. Furthermore, genetic knockdown of ITGB4 suggested that the ECM inhibiti

2024-11-23 | PXD058209 |

Chromatin architecture is indirectly regulated by CDK7 transcriptional activity

Project description:Cyclin Dependent Kinase 7 (CDK7) is the core catalytic subunit of Cyclin Activating Kinase (CAK), a complex that has dual roles in cell cycle progression and transcription. While several CDK7 inhibitors are efficacious in preclinical models of cancer and have entered clinical trials, the mechanism(s) by which CDK7 promotes proliferation and cell viability is not well understood. Using triple negative breast cancer (TNBC) as a model, we found that inhibiting CDK7, either genomically or pharmacologically, induces mitotic dysfunction. Live and static cell imaging revealed that CDK7 inhibition prolongs mitosis and induces chromatin bridge formation, DNA double strand breaks, and abnormal nuclear features, all of which are indicative of mitotic catastrophe and chromosome instability. Transcriptome analyses revealed that CDK7 is essential for maintaining condensin complex gene expression, suggesting that CDK7 may sustain chromatin configuration, a role that extends beyond its impact on super-enhancers. Indeed, inhibiting CDK7 alters chromatin architecture consistent with condensin disruption. Confirming the importance of condensin regulation by CDK7, genetic suppression of a core subunit of this complex, structural maintenance of chromosome 2 (SMC2), phenocopies CDK7 inhibition. We report an undescribed role of CDK7 in maintaining chromatin structure and chromosome stability, as well as promoting proper mitoses, by sustaining condensin expression.

2023-05-30 | GSE223785 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data