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DNA microarray analysis of the anti-inflammatory effects of PDTC on IL-6 signaling in HepG2 cells

ABSTRACT: Interleukin-6 (IL-6) is a proinflammatory cytokine that exerts a wide range of cellular, physiological and pathophysiological responses. Pyrrolidine dithiocarbamate (PDTC) antagonizes the cellular responsiveness to IL-6 through impairment in STAT3 activation and downstream signaling. Here, a transcriptional profiling was conducted as a basis for understanding the biological properties of PDTC in human HepG2 hepatocarcinoma cells. A global comparison of mRNA identified a highly significant difference of dysregulated gene expression transduced by PDTC versus IL-6 in HepG2 cells. Through an unbiased pathway analysis method, we have uncovered the mammalian target of rapamycin (mTOR) pathway together with rapid and dynamic alterations in REDD1 (regulated in development and DNA damage response 1) expression as one of the underlying molecular mechanisms responsible for IL-6 resistance to PDTC. Quantitative PCR and Western blot analyses validated the microarray data by showing the reciprocal pattern of REDD1 expression and subsequent mTOR inhibition after stimulation with PDTC relative to IL-6.

ORGANISM(S): Homo sapiens

PROVIDER: GSE14632 | GEO | 2012/01/05

SECONDARY ACCESSION(S): PRJNA112287

REPOSITORIES: GEO

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DNA microarray analysis of the anti-inflammatory effects of PDTC on IL-6 signaling in HepG2 cells

Project description:Interleukin-6 (IL-6) is a proinflammatory cytokine that exerts a wide range of cellular, physiological and pathophysiological responses. Pyrrolidine dithiocarbamate (PDTC) antagonizes the cellular responsiveness to IL-6 through impairment in STAT3 activation and downstream signaling. Here, a transcriptional profiling was conducted as a basis for understanding the biological properties of PDTC in human HepG2 hepatocarcinoma cells. A global comparison of mRNA identified a highly significant difference of dysregulated gene expression transduced by PDTC versus IL-6 in HepG2 cells. Through an unbiased pathway analysis method, we have uncovered the mammalian target of rapamycin (mTOR) pathway together with rapid and dynamic alterations in REDD1 (regulated in development and DNA damage response 1) expression as one of the underlying molecular mechanisms responsible for IL-6 resistance to PDTC. Quantitative PCR and Western blot analyses validated the microarray data by showing the reciprocal pattern of REDD1 expression and subsequent mTOR inhibition after stimulation with PDTC relative to IL-6. The HepG2 human hepatocarcinoma cell line (American Type Culture Collection) was routinely grown and maintained in Minimum Eagle's medium (MEM)/F12 (1:1) supplemented with 10% heat-inactivated fetal bovine serum, 50 units/ml penicillin and 50 ug/ml streptomycin under standard cell culture conditions at 37Â°C and 5% CO2 in a humid environment. Cells were seeded in 35- or 60-mm dishes and grown to ~90% confluence after which they were serum starved for 4 h followed by the addition of either vehicle, PDTC (50 ÂµM) or human recombinant IL-6 (20 ng/ml) for 2 replicates, labeled a and b, of the 5 time points: 0hr, 1hr, 2hr, 4hr and 8hr.

2012-01-05 | E-GEOD-14632 | biostudies-arrayexpress

Transcription profiling by array of yeast after treatment with pyrrolidine dithiocarbamate (PDTC) for 1, 3 or 5 hours

Project description:Effects of the compound Pyrrolidine dithiocarbamate (PDTC) on the gene expression of Saccharomyces cerevisiae after incubation times of 1, 3 and 5 hours with 75uM PDTC.

2010-08-12 | E-MEXP-2864 | biostudies-arrayexpress

MicroRNA expression from ARPE-19 cells: control and PDTC treated.

Project description:The cultured cell line ARPE-19 is frequently employed in studies of rpe function. Here we have identified the microRNAs expressed in RPE cells in the presence and absence of PDTC (pyrrolidine dithiocarbamate), an antioxidant. Analysis used microrNA extracted from untreated cells as a control for cells treated with PDTC

2010-07-24 | E-GEOD-23107 | biostudies-arrayexpress

MicroRNA expression from ARPE-19 cells: control and PDTC treated.

2010-07-24 | GSE23107 | GEO

Bortezomib inhibits mTOR pathway in multiple myeloma cells via induced expression of REDD1.

Project description:The combination of bortezomib and dexamethasone should become the reference induction treatment for multiple myeloma patients younger than 65 years. Pharmacogenomic profiles of genes involved in response to treatment may help to understand resistance. We performed gene expression profiling in 9 myeloma cell lines, incubated or not with bortezomib and dexamethasone for 6 hours. Supervised analysis identified significantly up regulated genes involved in stress responses. We focused on REDD1 a gene known to be rapidly induced by a wide variety of stress conditions and DNA damages. REDD1 expression was early and highly induced after bortezomib exposure. REDD1 induction was associated with the dephosphorylation of P70 S6 ribosomal kinase (P70S6K), a key substrate of mTOR. These effects were dependent upon cell line. REDD1 was overexpressed within two hours in bortezomib resistant cell lines in association with a cell size decrease. In sensitive cell lines, neither REDD1 induction nor morphological changes occurred. RNA interference mediated inhibition of REDD1 induction abrogates P70S6K dephosphorylation, early transitory cell size reduction and enhances sensitivity to bortezomib - dexamethasone. Our results suggest that mTOR regulation could be a resistance mechanism mediated by REDD1 expression in myeloma cells. Nine cell lines of multiple myeloma studied, incubated or not with bortezomib and dexamethasone, examined with spotted cDNA nylon membrane. Cell line and Code : JJN3 = Vel_1x; L363 = Vel_2x; LP1 = Vel_3x; MDN = Vel_4x; NCI = Vel_5x; RPMI = Vel_6x; SBN = Vel_7x; U266 = Vel_8x; XG1 = Vel_9x.

2010-02-14 | E-GEOD-11866 | biostudies-arrayexpress

REDD1 (regulated in development and DNA damage response 1) dissociates therapeutic and adverse effects of topical steroids in skin

Project description:Even though cutaneous atrophy is the major adverse effect of topical glucocorticoids, its molecular mechanisms are poorly understood. We found that glucocorticoids strongly increased the expression of REDD1 (regulated in development and DNA damage response 1), a stress-inducible inhibitor of mTOR, in mouse and human epidermis. We found that REDD1 knockout animals are partially resistant to glucocorticoid-induced epidermal and subcutaneous adipose atrophy which correlated with the protection of CD34+ follicular epithelial stem cells as well as p63+ keratinocyte progenitors in REDD1 knockout epidermis during chronic steroid treatment. At the same time, REDD1 knockout did not affect anti- inflammatory effect of glucocorticoids, as evaluated by ear edema test. Expression profiling revealed that ~ 50% of the glucocorticoid receptor (GR) target genes were not activated in epidermis of REDD1 knockouts, however, the negative effect of glucocorticoids on gene expression was similar to that in w.t. animals. Overall, our findings reveal a novel pathway in GR activation by its target gene/protein REDD1; and indicate an important role of REDD1 in glucocorticoid-induced skin atrophy, and maintenance of the epidermis and subcutaneous adipose. In addition, our findings form the foundation for the development of safer topical glucocorticoid treatment regimens by combining this therapy with REDD1 inhibitors.

2014-08-01 | GSE59151 | GEO

Bortezomib inhibits mTOR pathway in multiple myeloma cells via induced expression of REDD1.

2010-02-15 | GSE11866 | GEO

Homo sapiens

Project description:Bortezomib inhibits mTOR pathway in multiple myeloma cells via induced expression of REDD1.

| PRJNA105673 | ENA

HepG2 cells exposed to Benzo[a]pyrene for 6,12,18,24,36 and 48h.

Project description:HepG2 cells (human liver hepatocarcinoma) were exposed for 6 different time points (6,12,18,24,36 and 48h) to Benzo[a]pyrene (BaP) in duplicate.

2015-01-25 | E-MTAB-3251 | biostudies-arrayexpress

Genomic and Transcriptomic Hallmarks of Poorly-Differentiated and Anaplastic Thyroid Cancers

Project description:BACKGROUND. Poorly-differentiated (PDTC) and anaplastic (ATC) thyroid cancers are rare and frequently lethal tumors, which so far have not been subjected to comprehensive genetic characterization. METHODS. We performed next generation sequencing of 341 cancer genes in 117 PDTCs and ATCs, and a transcriptomic analysis of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas (TCGA) study of papillary thyroid cancers (PTC). RESULTS. ATCs have a greater mutation burden than PDTCs, and higher mutation frequency of TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits and histone methyltransferases. BRAF and RAS are the predominant drivers, and dictate remarkably distinct tropism for nodal vs. distant metastases in PDTC. RAS and BRAF sharply distinguish between PDTCs defined by the Turin (PDTC-Turin) vs. MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, are markedly enriched in PDTCs and ATCs, and have a striking pattern of co-occurrence with RAS. TERT promoter mutations are rare and subclonal in PTCs, whereas they are clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) shows a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs are BRAF-like irrespective of driver mutation. CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared to PDTC underscore their greater virulence and higher mortality. 37 tumor specimens, including 17 poorly-differentiated and 20 anaplastic thyroid cancers were expression-profiled with Affymetrix U133 plus 2.0 array

2016-02-15 | E-GEOD-76039 | biostudies-arrayexpress

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