Project 3

Impact of Cox-2 on protective effects of estrogen receptor beta (ERB) in prostate epithelial cellsv

Project leader: Donald Defranco, Ph.D.

Summary

Prostatic inflammation is a common feature of symptomatic benign prostatic hyperplasia (BPH) and may alter epithelial cell proliferation and tissue homeostasis in BPH through cytokine induction of proinflammatory signaling mediators such as cyclooxygenase-2 (Cox-2). Cox-2 is overexpressed in luminal epithelial cells of BPH tissue but predominantly in regions of chronic inflammation. One clinical trial reported only a short-term benefit of a Cox-2 inhibitor (i.e. nonsteroidal anti-inflammatory agents [NSAIDs] such as rofecoxib) in reducing LUTS symptoms when combined with a 5AR inhibitor. The mechanism responsible for the limited clinical effectiveness of Cox-2 inhibition is not known. In the human BPH-1 prostate epithelial cell line (which expresses high basal levels of Cox-2), pharmacologic or molecular ablation of Cox-2 expression limits the protective effects of ERß through selective disruptions in steroidogenic enzyme expression leading to a reduced production of ERß ligands from testosterone. We therefore hypothesize that the limited effectiveness of NSAIDs in current BPH clinical trials is due to disruptions in prostatic steroidogenic pathways that generate ligands for the tissue protective ERß. Four Aims are proposed to test this hypothesis: Aim 1 will determine the impact of Cox-2 on ERß ligand production in PrECs. Aim 2 will identify genome-wide basal and ERß-regulated gene expression patterns influenced by acute or long-term adaptive responses to Cox-2 overexpression in PrECs. Aim 3 will identify the impact of Cox-2 and ERß on targets relevant to polarized epithelial cell function in 3- dimensional cultures of PrECs and ERß knockout mice. Aim 4 will determine the impact of Cox-2 on ERß signaling in human prostate explants and a rodent model of prostatic inflammation

Personnel

Donald B. Defranco
Kai He
Liping Wang
Stacy Lynn Wendell
Uma R.Chandran