Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glucocorticoids-triggered CXCR4 signaling activates the PLC signalosome and promotes tumor resistance in B cell acute lymphoblastic leukemia

ABSTRACT: Approximately 20-25% of patients with acute lymphoblastic leukemia (ALL) relapse after initial chemotherapy and become resistant to glucocorticoids (GC). Although GC signaling act on well-defined transcriptional responses via GC receptors (GCR), there is emerging evidence that GC also mediate transcription-independent signaling events that appear to be very rapid. We previously established that rapid calcium-mediated cell survival signals, triggered by GC stimulation, are involved in the resistance to GC anti-leukemic effects. Furthermore, we demonstrated that chelating intracellular calcium with Bapta-AM or inhibiting downstream ERK1/2 signaling with PD98059 overcame GC resistance in ALL samples. Here, we investigate the potential role of PLC in GC resistance. We identified that Dexamethasone (Dex) induced cytosolic calcium release via a mechanism involving the cell surface receptor of CXCL12 (CXCR4) internalization and subsequent activation of PLC signalosome. We found that PLC inhibition was able to induce cell death in GC-resistant B-ALL cells by compromising the expression of genes in several metabolic pathways including cell cycle checkpoints, glycolysis and mitochondrial function. These results establish a role for nongenomic signaling in ALL resistance to GC and support identifying novel therapeutics targeting Ca2+ signaling to restore GC sensitivity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214990 | GEO | 2024/04/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

RNA-seq on CAR-T cells and CAR-T cells exposed to Nalm6 stimulation followed by treatment with DMSO, BAPTA and BTP-2

Project description:Chimeric antigen receptor (CAR) T cells are known to be potent in recognizing and eliminating tumor elimination, and effector functions. They induce marked responses in patients with refractory leukemia and lymphoma, but dysfunction of T cells is an inevitable obstacle for persistent curative effect. Extending the persistence of these cells without compromising their potency is supposed to improve treatment outcomes. We demonstrated that the SOCE (Store-Operated Calcium Entry) inhibitor BTP-2, rather than calcium chelator BAPTA-AM, diminished exhaustion and terminal differentiation of CAR-T cells both in tonic signaling and tumor antigen exposure models. And BTP-2 pretreated CAR-T cells showed improved antitumor potency and prolonged survival in NSG mice. To further investigate the biological impact of calcium signaling at the molecular level, we performed RNA-seq on CAR-T cells and CAR-T cells exposed to Nalm6 stimulation followed by treatment with DMSO, BAPTA and BTP-2.The high-throughput RNA sequencing (RNA-Seq) revealed that treatment with BTP-2 downregulates glycolysis pathway.

2021-11-19 | GSE178998 | GEO

Effects of ionomycin (final concentration of 2 µM) and BAPTA/AM (final concentration of 6 µM) on the RO82 W-1 human thyroid cell line

Project description:The goal of this study was to identifiy cellular pathways modified by calcium storing in cells presenting a glycolytic metabolism and a poor mitochondrial biogenesis. Keywords: calcium stress response in RO82 W-1 cells In duplicate, cells treated with ionomycin or BAPTA/AM during 96h compared to equivalent DMSO treated cells

2010-12-22 | E-GEOD-26237 | biostudies-arrayexpress

PD-L1 alteration in lung cancer affects tumorigenicity lung tumors

Project description:Cancer immunotherapy has focused on inhibitors of checkpoint proteins, such as Programmed Death Ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, we assumed that intrinsic and microenvironmental factors are involved. Among all non-immunological signaling pathways we surveyed in patients’ datasets, EGFR signaling best associated with high PD-L1. Correspondingly, active EGFRs stabilized PD-L1’s transcripts and depleting PD-L1 severely inhibited EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve recruitment of phospholipase C-g1 (PLC-g1) to a cytoplasmic motif of PD-L1, which enhances PLC-g1 activation by EGFR. Once stimulated, PLC-g1 activates calcium flux, RHO GTPases and protein kinase C, which promotes an aggressive phenotype. Furthermore, anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1. Our results portray PD-L1 as a molecular amplifier of EGFR signaling and lay the foundation for understanding resistance of EGFR+ tumors to immunotherapy.

2021-04-08 | GSE171650 | GEO

Decoding the pathogenesis of DBA by single-cell RNA-seq

Project description:Ribosomal protein dysfunction leads to diverse human diseases, including Diamond-Blackfan anemia (DBA). Despite the ubiquitous need for ribosomes in all cell types, the mechanisms underlying ribosomopathies manifesting with tissue-specific defects are still incompletely understood. In this study, at single cell resolution, we characterized the transcriptomes of highly-purified erythroid progenitors isolated from bone marrow (BM) of DBA patients, including non-treatment (NT), glucocorticoids (GC)-responsive (GCR) and GC-non-responsive (GCNR) patients. We uncovered that, rather than cell cycle arrest at G1 phase, erythroid progenitors in NT patients were compulsively entering cell cycle of S-phase, which triggered replication stress and consequently activated P53 pathway. In contrast, the cell cycle was restrained with compromised proliferation in GCR patients, but not GCNR counterparts, via elevating IFN pathway. More importantly, the combinational treatment of DEX and IFN exhibit a synergistic effect on erythrocytes from GCNR patients. Therefore, the innate cell cycle characteristics of erythroid progenitors is ascribed to the erythroid lineage specific defects of DBA. Controlling the cell cycle progression by IFN signaling underlies the GC clinical efficacy and combinational therapy of DEX and IFN holds great promise for GCNR patients.

2023-06-30 | GSE153618 | GEO

Glucocorticoids-triggered CXCR4 signaling activates the PLC signalosome and promotes tumor resistance in B cell acute lymphoblastic leukemia

Project description:Glucocorticoids-triggered CXCR4 signaling activates the PLC signalosome and promotes tumor resistance in B cell acute lymphoblastic leukemia

| PRJNA888042 | ENA

TNF induces Glucocorticoid Resistance by reshaping the GR Nuclear Cofactor Profile: Investigation of TNF mediated effects on the GR mediated gene expression

Project description:Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the anti-inflammatory properties of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a serious problem in the management of inflammatory diseases and occurs frequently. The strong pro-inflammatory cytokine TNF induces an acute form of GCR, not only in mice, but also in several cell lines, e.g. in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-induced GR-dependent gene expression. We report that TNF has a significant and broad impact on the transcriptional performance of GR, but no impact on nuclear translocation, dimerization or DNA binding capacity of GR. Proteome-wide proximity-mapping (BioID), however, revealed that the GR interactome is strongly modulated by TNF. One GR cofactor that interacts significantly less with the receptor under GCR conditions is p300. NFκB activation and p300 knockdown both reduce transcriptional output of GR, whereas p300 overexpression and NFκB inhibition revert TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis is supported by FRET studies. This mechanism of GCR opens new avenues for therapeutic interventions in GCR diseases

2019-05-06 | GSE124088 | GEO

TNF induces Glucocorticoid Resistance by reshaping the GR Nuclear Cofactor Profile: Investigation of TNF mediated effects on the GR-DNA binding

2019-05-06 | GSE123953 | GEO

Establishment of Primary Liver Cancer Organoids and Application on Sorafenib Resistance

Project description:Current in vitro models of primary liver cancer fail to recapitulate the key characteristics of original cancer. We construct the long-term organoids culture from tumor tissue of primary liver cancer (PLC) patients with varieties of subtypes. PLC organoids retain the histopathological features of originating tumor. Organoids transplantation proved that the tumorogenic potential and histological characteristics of PLC organoids are well preserved in vivo. PLC organoids are amenable for preclinical drug screening test and identification of mammalian target of rapamycin (mTOR) inhibitor compound as a potential therapeutic treatment for PLC. Besides, we also establish sorafenib-resistant hepatocellular carcinoma (HCC) organoids to clarify the mechanisms that drive resistance. In conclusion, PLC organoids models provide a platform for drug development for PLC and theoretical basis for HCC resistance.

2023-02-22 | GSE182593 | GEO

Ileal Crohn’s disease exhibits reduced activity of phospholipase C-β3 (PLC-β3)-dependent Wnt/b-catenin signaling pathway [16S rRNA]

Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.

2024-10-06 | GSE244936 | GEO

Ileal Crohn’s disease exhibits reduced activity of phospholipase C-β3 (PLC-β3)-dependent Wnt/b-catenin signaling pathway [microarray]

Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-β3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/β-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.

2024-10-06 | GSE244937 | 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