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Accession IconSRP074235

Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor ß (ERß) Response to 5a-reductase Inhibition in Prostate Epithelial Cells

Organism Icon Homo sapiens
Sample Icon 6 Downloadable Samples
Technology Badge IconIllumina HiSeq 2000

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Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor (AR) driven, inflammatory disorder affecting elderly men, include 5a-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 ß (ERß) ligands, 5AR inhibitors could potentially limit ERß 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 ERß and TGFß. Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative-feedback loop in TGFß and ERß 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 ERß action through its effect on the expression of a number of steroidogenic enzymes in the ERß-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 ERß. Overall design: Next-generation sequencing (n=3) of shRNA mediated knockdown of COX-2 or scrambled control in BPH-1 prostate epithelial cell line
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