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Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-reductase Inhibition in Prostate Epithelial Cells

ABSTRACT: Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor (AR) driven, inflammatory disorder affecting elderly men, include 5α-reductase (5AR) inhibitors (i.e. dutasteride and finasteride) to block the conversion of testosterone to the more potent AR ligand dihydrotestosterone (DHT). Since DHT is the precursor for estrogen receptor β (ERβ) ligands, 5AR inhibitors could potentially limit ERβ activation, which maintains prostate tissue homeostasis. We have uncovered signaling pathways in BPH-derived prostate epithelial cells (BPH-1) that are impacted by 5AR inhibition. The induction of apoptosis and repression of the cell-adhesion protein E-cadherin by the 5AR inhibitor, dutasteride, requires both ERβ and TGFβ. Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative-feedback loop in TGFβ and ERβ signaling pathways as evidenced by the potentiation of apoptosis induced by dutasteride or finasteride upon pharmacological inhibition or shRNA-mediated ablation of COX-2. Concurrently, COX-2 positively impacts ERβ action through its effect on the expression of a number of steroidogenic enzymes in the ERβ-ligand metabolic pathway. Therefore, effective combination pharmacotherapies, which have included non-steroidal anti-inflammatory drugs, must take into account biochemical pathways affected by 5AR inhibition and opposing effects of COX-2 on the tissue protective action of ERβ.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80979 | GEO | 2016/05/12

SECONDARY ACCESSION(S): PRJNA320221

REPOSITORIES: GEO

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Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor Î² (ERÎ²) Response to 5Î±-reductase Inhibition in Prostate Epithelial Cells

Project description:Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor (AR) driven, inflammatory disorder affecting elderly men, include 5Î±-reductase (5AR) inhibitors (i.e. dutasteride and finasteride) to block the conversion of testosterone to the more potent AR ligand dihydrotestosterone (DHT). Since DHT is the precursor for estrogen receptor Î² (ERÎ²) ligands, 5AR inhibitors could potentially limit ERÎ² activation, which maintains prostate tissue homeostasis. We have uncovered signaling pathways in BPH-derived prostate epithelial cells (BPH-1) that are impacted by 5AR inhibition. The induction of apoptosis and repression of the cell-adhesion protein E-cadherin by the 5AR inhibitor, dutasteride, requires both ERÎ² and TGFÎ². Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative-feedback loop in TGFÎ² and ERÎ² signaling pathways as evidenced by the potentiation of apoptosis induced by dutasteride or finasteride upon pharmacological inhibition or shRNA-mediated ablation of COX-2. Concurrently, COX-2 positively impacts ERÎ² action through its effect on the expression of a number of steroidogenic enzymes in the ERÎ²-ligand metabolic pathway. Therefore, effective combination pharmacotherapies, which have included non-steroidal anti-inflammatory drugs, must take into account biochemical pathways affected by 5AR inhibition and opposing effects of COX-2 on the tissue protective action of ERÎ². Next-generation sequencing (n=3) of shRNA mediated knockdown of COX-2 or scrambled control in BPH-1 prostate epithelial cell line

2016-05-12 | E-GEOD-80979 | biostudies-arrayexpress

The¬¬¬ androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer

Project description:Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.

2024-01-30 | PXD047997 | Pride

Co-clinical analysis of a genetically-engineered mouse model and human prostate cancer reveals significance of NKX3.1 expression for response to 5α-reductase inhibition (Mouse Finasteride Prostate RNASeq)

Project description:Analysis of transcriptome from 12 month old finasteride (and vehicle) treated mouse prostatic tissue Prostate tissue from 12 month old Nkx3.1+/+ and Nkx3.1-/- mice treated with finasteride (or vehicle) was harvested, and snap frozen for subsequent molecular analysis

2017-04-04 | GSE92999 | GEO

RNA-Seq with DHT induction and/or GSK treatment at 24, 48 hrs and 2 weeks

Project description:The major pioneer factor activity of FOXA1 in PCa is to facilitate AR recruitment to androgen-regulated enhancers. Therefore, we hypothesized that the decreased FOXA1 binding and enhancer availability by LSD1 inhibition may result in the impairment of subsequent AR recruitment to enhancers. To globally test this hypothesis, we performed AR ChIP-seq in LNCaP cells treated with an LSD1 inhibitors. Consistent with previous reports, DHT treatment can dramatically induce AR binding to chromatin. Significantly, LSD1 inhibitor treatment in presence of DHT stimulation markedly decreased the total number of AR binding peaks and their intensity. We further assessed the impact of LSD1 inhibition on overall AR transcriptional output using RNA-seq data.

2019-09-29 | GSE114267 | GEO

AR ChIP-seq with DHT induction and GSK treatment

2019-09-29 | GSE114266 | GEO

Transcription profiling of human LNCaP cells to investigate androgen receptor mediated gene expression by a sequence-specific DNA binding polyamide

Project description:Androgen Receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. We have designed a sequence-specific DNA binding polyamide (1) that targets the consensus androgen response element (ARE). This polyamide binds the PSA promoter ARE, inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic anti-androgen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of AR-DNA binding by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity. A polyamide (2) that targets a different DNA sequence is included as a control. Experiment Overall Design: DHT (dihydrotestosterone)-stimulated LNCaP cells that were treatment with polyamide 1, polyamide 2, bicalutamide were compared to control cells that were also DHT-stimulated. Cells not stimulated with DHT were also compared to the DHT-stimulated controls. Three biological replicates were included for each treatment/condition except the no-DHT induced controls, which were in biological duplicate.

2009-04-23 | E-GEOD-7708 | biostudies-arrayexpress

Proteomics via immune-precipitation assisted Mass-Spectrometry of Androgen receptor in INS1 cells.

Project description:IP- Mass Spec of INS1 cells treated with DHT or GLP1 and then subjected to IP of AR protein and subsequent mass spec to identify binding partners of AR relevant to Insulin signaling and secretion.

2023-04-17 | PXD041592 | Pride

Expression status of mRNA for sex hormone receptors in human dental pulp cells and the response to sex hormones in the cells

Project description:Objectives: Sex hormone receptors are reported to be present in human dental pulp (HDP) cells. The purpose of this study was to examine the biological significance of estrogen and androgen receptors (ER and AR, respectively) in HDP cells. Design: We isolated HDP cells expressing ER- and AR-mRNAs and investigated the expression status of the receptors and the response to sex hormones in the cells. Results: HDP cells expressing ER- and/or AR-mRNAs had the ability to form alizarin red S-positive nodules in which calcium and phosphorus were deposited in vitro and to differentiate into odontoblasts-like cells and dentin-like tissue in vivo. Individual clones isolated from HDP cells exhibited a different expression pattern of mRNA for ER and AR. Some clones expressed ERα- and/or ERβ-mRNAs and the others coexpressed ER- and AR-mRNAs. Using the Ingenuity software, we found that 17β-estradiol (E2) and dihydrotestosterone (DHT) could act directly on HDP cells through ER- or androgen signaling-mediated mechanisms. E2 or DHT stimulated the mRNA expression for genes related to odontogenesis of dentin-containing teeth and odontoblast differentiation, suggesting that ER and AR in HDP cells may be involved in dentinogenesis. Conclusions: Our findings provide new insights into the biological significance of sex hormone receptors in HDP cells.

2013-03-28 | GSE44677 | GEO

Targeting androgen receptor phase separation to overcome antiandrogen resistance mediated by "pharmacological condensates"

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2021-10-05 | GSE185223 | GEO

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