Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Death receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

ABSTRACT: Apo2L/TRAIL stimulates cancer-cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyl transferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non-small cell lung carcinoma and melanoma cell lines (P < 0.00009; n=83), and up to 30% of samples from various human malignancies displayed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-GalNAc-Gal-Sialic acid structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptosis signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a novel link between death receptor O-glycosylation and apoptosis signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy. Keywords: cell type comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE8332 | GEO | 2007/08/31

SECONDARY ACCESSION(S): PRJNA101327

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of human pancreatic carcinoma, non-small cell lung carcinoma and melanoma cell lines reveals death receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Project description:Apo2L/TRAIL stimulates cancer-cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyl transferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non-small cell lung carcinoma and melanoma cell lines (P < 0.00009; n=83), and up to 30% of samples from various human malignancies displayed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-GalNAc-Gal-Sialic acid structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptosis signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a novel link between death receptor O-glycosylation and apoptosis signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy. Experiment Overall Design: Gene expression for untreated cell lines analyzed. Some cell lines have one replicate profile, some two (Samples with 2 CEL files). Normalized data for replicates was averaged. Analysis involved a regularized t-test to identify genes with expression differences between Apo2L sensitive and resistant lines.

2008-06-16 | E-GEOD-8332 | biostudies-arrayexpress

Proteomic analysis of TRAIL-induced endogenous RIPK3-dependent necrosome complex

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a well-known inducer of apoptosis via formation of the primary death-inducing signaling complex (TRAIL-DISC) at the level of membrane death receptors (DR4 and DR5) which recruit successively FADD and caspase-8. TRAIL can also induce necroptosis when caspases are inhibited. Necroptosis is a regulated cell death dependent on the formation of a cytosolic necrosome complex which includes RIPK1, RIPK3 and MLKL proteins. Elucidating the molecular mechanisms involved in TRAIL-induced necroptosis might provide new insights into the TRAIL death signaling pathway. Here, we report the analysis by mass spectrometry of endogenous RIPK3-dependent necrosome complex constituents upon necroptosis induced by TRAIL/z-VAD/Birinapant (TzB) in HT29 cells. Besides characterization of RIPK1, RIPK3, MLKL, FADD, caspase-8, we find TRIM21 as a new constituent of the necrosome complex. Moreover RIPK1, RIPK3, MLKL, P-MLKL, FADD, caspase-8 and TRIM21 are also found associated to the native TRAIL-DISC upon TzB stimulation showing initiation of the necrotic pathway at the level of TRAIL death receptors in HT29 cells. Finally, TRIM21 may positively modulate necroptosis induction by downregulating NF-kB activation.

2021-03-18 | PXD003383 | Pride

Acquired resistance of Jurkat cells to TNF-related apoptosis-inducing ligand (TRAIL): a role for histone deacetylase inhibitors as powerful apoptosis sensitizer.

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other “death receptor” ligands may explain not only the inability of TRAIL and TRAIL “death receptor” agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell – mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). Irrespective of molecular changes histone deacetylase inhibitors (HDACi), such as suberoylanilide-hydroxamic acid (SAHA, vorinostat), were able to restore sensitivity of all three TRAIL-resistant clones to TRAIL. Gene expression analysis of TR1 clone treated with SAHA 1microM for 12 hours compared to untreated TR1 clone showed significant decrease in expression of CFLAR/cFLIP (0.71; p=0.006), BIRC5/survivin (0.80; p=0.024) and BID (0.66; p<0.001). Expression of both TRAIL “death” receptors DR4 (1.57; p<0.001) and DR5 (1.47; p=0.002) were significantly increased compared to untreated TR1 cells. The mRNA expression of caspases-2,-3,-8,-9,-10 did not significantly change with the SAHA treatment.

2016-06-15 | GSE38745 | GEO

Acquired resistance of Jurkat cells to TNF-related apoptosis-inducing ligand (TRAIL): a role for histone deacetylase inhibitors as powerful apoptosis sensitizer.

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other âdeath receptorâ ligands may explain not only the inability of TRAIL and TRAIL âdeath receptorâ agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell â mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). Irrespective of molecular changes histone deacetylase inhibitors (HDACi), such as suberoylanilide-hydroxamic acid (SAHA, vorinostat), were able to restore sensitivity of all three TRAIL-resistant clones to TRAIL. Gene expression analysis of TR1 clone treated with SAHA 1microM for 12 hours compared to untreated TR1 clone showed significant decrease in expression of CFLAR/cFLIP (0.71; p=0.006), BIRC5/survivin (0.80; p=0.024) and BID (0.66; p<0.001). Expression of both TRAIL âdeathâ receptors DR4 (1.57; p<0.001) and DR5 (1.47; p=0.002) were significantly increased compared to untreated TR1 cells. The mRNA expression of caspases-2,-3,-8,-9,-10 did not significantly change with the SAHA treatment. Total cellular RNA was isolated from biologic duplicates of untreated Jurkat cells (WT), TRAIL resistant Jurkat cell clone (TR1) and 1 ÂµM and 0.5 ÂµM suberoylanilide-hydroxamic acid (SAHA, vorinostat) treated TR1 cell clones for 12 hours. Jurkat cell line subclones TR1was established by selective pressure of TRAIL 1000 ng/mL on Jurkat cells over the period of 12 weeks.

2016-06-15 | E-GEOD-38745 | biostudies-arrayexpress

The probiotic Propionibacterium freudenreichii as a new adjuvant for TRAIL-based therapy in colorectal cancer

Project description:TRAIL (TNF-Related Apoptosis Inducing Ligand) is a well-known apoptosis inducer, which activates the extrinsic death pathway. It is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by resistance which occurs in approximately 50% of cancer cells. SCFA (Short Chain Fatty Acids) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate/acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. We hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, boosted pro-apoptotic gene expression in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and on caspase-8, caspase-9 and caspase-3 activation, was more lethal on cancer cells than on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented only by P. freudenreichii induced apoptosis of HT29 cells and enhanced cytotoxic activity of TRAIL, as did P. freudenreichii culture supernatants or its metabolites SCFA. These results open new perspectives for the use of food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer.

2016-02-01 | GSE67033 | GEO

Homo sapiens

Project description:Death receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

| PRJNA101327 | ENA

Transcription profiling of human TRAIL-resistant metastatic vs primary TRAIL-sensitive melanoma cells

Project description:T1 and G1 are the two melanoma cell lines, established from primary tumor (T1) and lymph node metastases (G1) of a 77 years old male patient. While G1 cells were resistant to TRAIL (TNF-related apoptosis-inducing ligand) mediated cell death, T1 cells exhibited a high dose- and time-dependent sensitivity to TRAIL. Cells were treated with or without of two doses (0.2 and 1ug/ml) of TRAIL for 24 h. Gene expression of each sample vs pool was measured. TRAIL-resistant metastatic G1 vs primary TRAIL-sensitive T1 was compared.

2006-01-01 | E-MEXP-247 | biostudies-arrayexpress

RNA seq on NEO2734, CFI-400945 or SASP treated cells

Project description:Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies. However, lack of broadly acting senolytic drugs remains a challenge. Using inducible CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify here loss of the death receptor inhibitor cFLIP as a universal vulnerability of senescent cancer cells. Senescent cancer cells are primed for apoptotic death by NF-kB-mediated upregulation of death receptor DR5 and its ligand TRAIL but are protected from death by increased cFLIP. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of all senescent cancer cells tested. We validate this ?one-two punch? cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.

2022-08-24 | GSE191255 | GEO

CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade

Project description:Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death (ICD) of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TNF-related apoptosis-inducing ligand (TRAIL), 5-fluorouracil (5-FU) chemotherapy, and anti-PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.

2022-02-09 | GSE196276 | GEO

Expression data from MTDH knockdown in the Hec50co endometrial cancer cell line

Project description:Understanding the molecular underpinnings of chemoresistance is vital to design therapies to restore chemosensitivity. In particular, metadherin (MTDH) has been demonstrated to have a critical role in chemoresistance. Over-expression of MTDH has recently been implicated in poor clinical outcome in breast cancer, neroblastoma, hepatocellular carcinoma and prostate cancer. In this present study, we focused on the therapeutic benefit of MTDH depletion to restore sensitivity to cell death mediated by a combinatorial therapy of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL), which promotes death of cancerous cells of the human reproductive tract, and histone deacetylase (HDAC) inhibitors, which have been shown to increase sensitivity of cancer cells to TRAIL-induced apoptosis. Our data indicate that depletion of MTDH in endometrial cancer cells results in sensitization of cells that were previously resistant to cell death mediated by combinatorial treatment with TRAIL and HDAC inhibitor LBH589. MTDH was found to be involved in G2/M checkpoint regulation in response to LBH589 alone or LBH589 in combination with TRAIL, suggesting that MTDH functions at the cell cycle checkpoint to accomplish resistance.Using microarray technology, we identified 57 downstream target genes of MTDH, including Calbindin 1 and Galectin 1, which may contribute to MTDH-mediated resistance to combinatorial TRAIL and HDAC inhibitor targeted therapy. Inhibition of PDK1,AKT phosphorylation and increase Bim expression and XIAP degradation may result in sensitivity to cell death induction in MTDH depleted Hec50co cells by TRAIL and LBH 589 combination treatment. These findings indicate that depletion of MTDH is a potentially novel avenue for effective cancer therapy. The microarray was performed on three biological triplicates as well as three experimental triplictes of stable knockdown and control cells. MTDH was knocked down using a shRNA.

2010-12-17 | E-GEOD-26134 | biostudies-arrayexpress

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