Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of the Aryl Hydrocarbon Receptor - Polyamine Biosynthesis Axis Suppresses Multiple Myeloma and prostate cancer progression

ABSTRACT: Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of xenobiotic response. Our study revealed that AHR also positively regulated intracellular polyamine production via direct transcriptional activation of two genes (ODC1 and AZIN1) involved in polyamine biosynthesis and control, respectively. In multiple myeloma patients, AHR levels inversely correlated with survival, suggesting that AHR inhibition may be beneficial for treatment of this disease .We identified clofazimine, an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of multiple myeloma (Vk*Myc mice) and in immunocompromised mice bearing multiple myeloma cell xenografts, revealed high efficacy of clofazimine comparable to that of bortezomib, a first-in-class proteasome inhibitor used for treatment of multiple myeloma. This study identified a previously unrecognized regulatory axis between AHR and polyamine metabolism and discovered clofazimine as an inhibitor of AHR and a potentially clinically-relevant anti-multiple myeloma agent. RNA-seq: human multiple myeloma MM1S and human normal fibroblasts WI38 cells -/+ CLF 2-4uM for 24hrs; -/+ shAHR

ORGANISM(S): Homo sapiens

PROVIDER: GSE117160 | GEO | 2018/07/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription

Project description:Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against C. rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that cell-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as augments autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.

2022-10-06 | GSE214152 | GEO

Gene expression profile in multiple myeloma tumors from Vk*MYC mice

Project description:Myeloma tumors arose in Vk*MYC mice share gene expression profile with multiple myeloma tumors from human patients

2020-02-20 | GSE111921 | GEO

Evaluation of CNAs in multiple myeloma tumors from Vk*MYC mice

Project description:Myeloma tumors arose in Vk*MYC mice share copy number abnormalities with multiple myeloma tumors from human patients

2020-02-20 | GSE110954 | GEO

H3K4me3 ChIP in multiple myeloma MM1S cells in the presence and absence of KDM5-C70

Project description:In this experiment we demonstrate the use of an inhibitor of the KDM5 family of histone demethylases, KDM5-C70, on H3K4me3 marks in the multiple myeloma cell line MM1S. KDM5-C70 increases H3K4me3 in a global fashion across the genome. Examination of H3K4me3 mark across MM1S cells treated with either KDM5-C70 or vehicle control

2016-04-05 | E-GEOD-78206 | biostudies-arrayexpress

Multiple myeloma tumors from Vk*MYC mice

Project description:Multiple myeloma tumors from Vk*MYC mice

| PRJNA438547 | ENA

Identification of sialyl Lewisa/x-modified surface proteins in Multiple Myeloma cells by LC-MS

Project description:The project aims at identifying surface proteins that are modified by the tetrasaccharide sialyl Lewisa/x and therefore serve as selectin ligands in Multiple Myeloma. To that end, we have performed an immunoprecipitation using the Heca452 antibody (which recognizes sialyl Lewisa/x-related structures) and a matched isotype control on membrane-enriched fractions that have been generated from the sialyl Lewisa/x-enriched and parental Multiple Myeloma cell line MM1S and RPMI8226. Using this approach, we have been able to identify candidate proteins that may function as selectin ligands in myeloma.

2024-01-23 | PXD046178 | Pride

H3K4me3 ChIP in multiple myeloma MM1S cells in the presence and absence of KDM5-C70

2016-04-05 | GSE78206 | GEO

Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDA) cells have a distinct dependence on de novo ornithine synthesis from glutamine via ornithine aminotransferase (OAT), which supports polyamine synthesis and is required for tumor growth. This directional OAT activity is normally largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginase (ARG) to generate arginine-derived ornithine, the substrate for polyamine synthesis. This dependence associates with arginine depletion in PDA tumor microenvironment, and is driven by mutant KRAS, which induces the expression of OAT and polyamine synthesis enzymes, including the rate-limiting enzyme ornithine decarboxylase-1 (ODC1). Loss of OAT, but not ARG2, largely mimics loss of ODC1, altering the transcriptional profiles in PDA cells, which in turn correlate with alterations in open chromatin states.

2023-01-01 | GSE193411 | GEO

DFMO effect on Th17 and iTreg cells (ATAC-Seq)

Project description:We studied the effects of polyamine pathway inhibitors on differentiation of nonpathogenic Th17 cellsin vitro. Here, we used difluoromethylornithine (DFMO), an irreversible inhibitor of ODC1, the enzyme that catalyzes the conversion of ornithine to putrescine.

2021-07-06 | GSE165088 | GEO

Microarray analysis of a multiple myeloma cell line, MM1S, treated with adenosine A2A and Beta-2 Adrenergic Receptor agonists in combination with dexamethasone

Project description:We have used an agnostic approach to identify drug combinations by using combination high throughput screening (cHTS) technology and make the surprising discovery that adenosine A2A and beta-2 adrenergic receptor agonists are highly synergistic, selective and novel agents that enhance glucocorticoid activity in B-cell malignancies. We used the microarray study to understand the synergistic mechanism between dexamethasone and A2A receptor agonist or Beta-2 Adrenergic receptor agonist in a multiple myeloma cell line, MM1S. MM1S cells were treated with CGS-21680 or Salmeterol alone, or in combination with dexamethasone for six hours for RNA extraction and hybridization on Affymetrix microarrays.

2012-03-31 | E-GEOD-30644 | 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