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Dexamethasone treatment of VCaP prostate cells

ABSTRACT: The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. We identified glucocorticoid receptor (GR) activity as modulator of enzalutamite sensitivity in the VCaP prostate cancer cell line. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. These expression profiling data demonstrate that GR transcriptional activity overlaps with that of AR in the VCAP model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51872 | GEO | 2013/12/27

SECONDARY ACCESSION(S): PRJNA225672

REPOSITORIES: GEO

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Dexamethasone treatment of VCaP prostate cells

Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. We identified glucocorticoid receptor (GR) activity as modulator of enzalutamite sensitivity in the VCaP prostate cancer cell line. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. These expression profiling data demonstrate that GR transcriptional activity overlaps with that of AR in the VCAP model. VCAP cells growing in complete media were treated with the indicated drugs in biological triplicates for 24 hours prior to harvest.

2013-12-27 | E-GEOD-51872 | biostudies-arrayexpress

Transcriptome analysis of VCaP xenografts resistant to dual therapy with abiraterone and enzalutamide

Project description:We report RNA sequencing data on serial biopsies of prostate cancer VCaP xenografts as the tumors pass from androgen-sensitivity (Pre-Cx), to castration resistance (CRPC, castration resistant prostate cancer), onto resistance to dual therapy with abiraterone plus enzalutamide (AER). From comparison of these RNAseq data sets, we were able to determine differentially expressed genes between the AER/CRPC and Pre-Cx states that could mediate resistance to androgen deprivation therapies.

2018-12-26 | GSE109708 | GEO

RNA-seq analysis regarding antiandrogen (enzalutamide) effect on gene expression in castration-resistant prostate cancer (CRPC) xenograft model

Project description:VCaP prostate cancer xenografts grown in castrated mice were treated with antiandrogen (enzalutamide), and samples were obtained during treatment response (Enza I: 5 days after initiation of the treatment) and after the treatment resistance had occurred (Enza II: 47 days after initiation of the treatment).

2022-05-02 | GSE147541 | GEO

LNCAP/AR and a LnCAP/AR subline (LREX') with acquired resistance to 2nd generation antiandrogens

Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Using the LnCaP/AR xenograft model, we identified induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors. From a resistant xenograft tumor, we derived a GR expressing resistant subline called LREX' which maintains the resistant phenotype. mRNA expression was used to characterize resistant tissues. LnCaP/AR cells were injected into castrate mice and tumors were established. Mice were then treated with vehicle (Con), 4 days of anti-androgen (ARN-509 10mgkg), or were maintained on anti-androgen (10mg/kg ARN-509 or enzalutamide) until emergence of resistance. Resistant tissues continued to be exposed to anti-androgen through time of harvest. LREX' (LnCaP/AR Resistant to Enzalutamide Xenograft Derived) was derived from an enzalutamide resistant xenograft and was re-injected into castrate mice undergoing continual treatment with enzalutamide. The GR probe on the Illumina array failed to detect GR expression. Therefore, GR expression as determined by qPCR is annotated separately. Of the 10 control tissues, 8 were analyzed twice (technical duplicates annotated as A and B).

2013-12-27 | E-GEOD-51873 | biostudies-arrayexpress

Androgen and Glucocorticoid stimulation of LREX' cells in vitro

2013-12-27 | E-GEOD-51871 | biostudies-arrayexpress

Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer

Project description:In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

2017-09-11 | GSE103449 | GEO

Androgen and Glucocorticoid stimulation of LREX' cells in vitro

2013-12-27 | GSE51871 | GEO

LNCAP/AR and a LnCAP/AR subline (LREX') with acquired resistance to 2nd generation antiandrogens

2013-12-27 | GSE51873 | GEO

Linking prostate cancer cell AR heterogeneity to distinct castration and Enzalutamide responses

Project description:Molecular mechanisms underlying resistance to androgen deprivation therapy (ADT) and, in particular, to antiandrogen Enzalutamide, in treating castration-resistant prostate cancer (CRPC), remain incompletely understood. Through screening >120 CRPC patient samples, we observed 3 expression patterns of androgen receptor (AR) protein: primarily nuclear (nuc-AR), mixed nuclear/cytoplasmic expression (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling in 4 models (i.e., LNCaP, VCaP, LAPC4, and LAPC9) recapitulated the 3 AR expression patterns in castration-resistant tumors developed from parental androgen-dependent tumors. Strikingly, although the 3 CRPC models that retained AR expression (LNCaP, VCaP, and LAPC4) responded, to different levels and in different kinetics, to Enzalutamide, the AR-/lo LAPC9 CRPC was completely refractory to Enzalutamide. By combining whole-genome RNA-Seq and biochemical analyses together with experimental combinatorial therapy in the LNCaP and LAPC9 models, we identified BCL-2 as a critical therapeutic target in both AR+/hi and AR-/lo, Enzalutamide-resistant CRPC models.

2018-08-01 | GSE88752 | GEO

GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance

Project description:Genomic amplification of the androgen receptor (AR) is an established mechanism of antiandrogen resistance in prostate cancer. Here we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1. We demonstrate 100-fold heterogeneity in AR output within cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting p300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo. Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.

2019-02-27 | GSE120720 | GEO

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