Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

New compounds triggering endoplasmic reticulum stress exert anti-melanoma effects and overcome BRAF inhibitor resistance

ABSTRACT: We discovered and developed a new series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all tested melanoma cells including those isolated from patients and those that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases endoplasmic reticulum (ER) stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79071 | GEO | 2016/06/01

SECONDARY ACCESSION(S): PRJNA314870

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

New compounds triggering endoplasmic reticulum stress exert anti-melanoma effects and overcome BRAF inhibitor resistance

Project description:We discovered and developed a new series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all tested melanoma cells including those isolated from patients and those that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases endoplasmic reticulum (ER) stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms. Profiling of 3 human melanoma cell lines (SKMel28, Mel501, A375) treated with HA15 at 10 uM or with DMSO was performed using whole genome human microarrays. Cells were incubated with DMSO or HA15 for 6h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment, total of 6 samples.

2016-06-01 | E-GEOD-79071 | biostudies-arrayexpress

Induction of ER stress in the colon cancer cell line LS174 with SubAB

2013-02-24 | GSE28466 | GEO

Induction of ER stress in the colon cancer cell line LS174 with SubAB

Project description:To assess the effect of activation of the unfolded protein response (UPR) in colon cancer cell lines, we treated cells with the AB5 subtilase cytotoxin (SubAB). This proteolytically cleaves the 78-kDa glucose-regulated protein (GRP78; also known as HSPA5 or BiP) inside the endoplasmic reticulum. We find that the WNT signaling pathway is highly affected upon treatment with SubAB. 500,000 cells were plated in a 10 cm2 plate, and the following day, treated for 20 hrs with SubAB or the control (SubAA272B), and then harvested. Three independent biological replicates per treatment.

2013-02-24 | E-GEOD-28466 | biostudies-arrayexpress

EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer

Project description:Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5, also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis.

2023-10-24 | PXD039998 | Pride

2',3,5-Trimethoxychalcone (MC-23)-induced gene expression in MiaPaCa2 cells

Project description:2',3,5-Trimethoxychalcone (MC-23) triggers apoptosis independently of p53 in MiaPaCa2 cells. To understand the mechanism of action of MC-23, we analysed the gene expression profiles in MiaPaCa2 cells treated with 10 μM MC-23 for 6, 12, or 24 h using the Agilent human 44K oligonucleotide V2 microarray. Out of the 34,127 genes in the array, MC-23 upregulated ~3% and downregulated. Notably, a large number of genes associated with apoptosis (such as BAX, BAK), chaperones (such as HSPA1/HSP70, HSPA5/GRP78/BiP), and the unfolded protein response (such as IRE1α, CHOP/DDIT3/GADD153, XBP1, ATF4, ATF6) were highly up-regulated by MC-23 treatment, suggesting that ER stress is associated with MC-23-induced apoptosis.

2014-01-21 | GSE54225 | GEO

2',3,5-Trimethoxychalcone (MC-23)-induced gene expression in MiaPaCa2 cells

Project description:2',3,5-Trimethoxychalcone (MC-23) triggers apoptosis independently of p53 in MiaPaCa2 cells. To understand the mechanism of action of MC-23, we analysed the gene expression profiles in MiaPaCa2 cells treated with 10 M-NM-<M MC-23 for 6, 12, or 24 h using the Agilent human 44K oligonucleotide V2 microarray. Out of the 34,127 genes in the array, MC-23 upregulated ~3% and downregulated. Notably, a large number of genes associated with apoptosis (such as BAX, BAK), chaperones (such as HSPA1/HSP70, HSPA5/GRP78/BiP), and the unfolded protein response (such as IRE1M-NM-1, CHOP/DDIT3/GADD153, XBP1, ATF4, ATF6) were highly up-regulated by MC-23 treatment, suggesting that ER stress is associated with MC-23-induced apoptosis. Global gene expression profile was measured at 6, 12, and 24 hours after exposure to doses of 10 M-NM-<M MC-23 in MiaPaCa2 cells. Three independent experiments were performed at each time using different experiments.

2014-01-21 | E-GEOD-54225 | biostudies-arrayexpress

Anti-proliferative effects of continued mitogen activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma: Implications for treatment beyond disease progression

Project description:Inhibitors of the MAPKs, BRAF and MEK, induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6-7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now demonstrate that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signalling, decrease in BrdU incorporation and S-phase inhibition. This cytostatic effect was also associated diminished levels of cyclin D1 and p-pRb.. Two short-term melanoma cultures generated from resistant tumour biopsies also responded to MAPK inhibition with comparable inhibitory changes in proliferation and MAPK signalling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy. Total RNA obtained from melanooma cell lines treated for 24h with dabrafenib, trametinib or combination of dabrafenib and trametinib

2013-06-30 | E-GEOD-44753 | biostudies-arrayexpress

Impact of BRAF kinase inhibitors on miRNomes and transcriptomes of melanoma cells (gene expression dataset)

Project description:Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. miRNA and gene expression were assessed by microarray analyses of the BRAF inhibitor sensitive melanoma cells A375, IGR37, and 501Mel, as well as on the vemurafenib (PLX4032) - resistant cells A375_XP, IGR37_XP, 501Mel_XP, and dabrafenib (GSK2118436) - resistant cells A375_GP, IGR37_GP, 501Mel_GP. For each cell line the microarray experiment was performed in duplicates.

2017-03-06 | E-MTAB-5511 | biostudies-arrayexpress

Impact of BRAF kinase inhibitors on miRNomes and transcriptomes of melanoma cells (miRNA dataset)

2017-03-06 | E-MTAB-5510 | biostudies-arrayexpress

Braf inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia, and exert anti-leukemic activity

Project description:Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL. Analysis of differential gene expression in primary leukemic cells purified from peripheral blood of 6 HCL patients (from A to F), treated with Vemurafenib 1000 nM, in comparison with vehicle-treated (DMSO) HCL cells, for 48 hours or/and 72 hours. 24 gene expression profiles were analysed.

2014-12-12 | E-GEOD-63790 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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