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 ER through selective disruptions in steroidogenic enzyme expression leading to a reduced production of ER 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 ER.
Four Aims are proposed to test this hypothesis:
Aim 1 will determine the impact of Cox-2 on ER ligand production in PrECs.
Aim 2 will identify genome-wide basal and ER-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 ER on targets relevant to polarized epithelial cell function in 3- dimensional cultures of PrECs and ER knockout mice.
Aim 4 will determine the impact of Cox-2 on ER signaling in human prostate explants and a rodent model of prostatic inflammation
Benign prostate hyperplasia (BPH) is a common disorder that affects ageing men and can trigger lower urinary tract symptoms. While inflammation contributes to symptomatic BPH, potent anti-inflammatory drugs such as NSAIDs are only minimally effective. This project examines the molecular basis for the lack of efficacy of NSAIDs for treatment of BPH and will reveal new molecular and metabolic biomarkers that could both predict response to NSAIDs and lead to development of new agents that enhance anti-inflammatory drug action in BPH patients.
| Tyagi, Pradeep; Motley, Saundra S; Koyama, Tatsuki et al. (2018) Molecular correlates in urine for the obesity and prostatic inflammation of BPH/LUTS patients. Prostate 78:17-24 |
| Li, Feng; Pascal, Laura E; Zhou, Jianhua et al. (2018) BCL-2 and BCL-XL expression are down-regulated in benign prostate hyperplasia nodules and not affected by finasteride and/or celecoxib. Am J Clin Exp Urol 6:1-10 |
| Mizoguchi, Shinsuke; Mori, Kenichi; Wang, Zhou et al. (2017) Effects of Estrogen Receptor ? Stimulation in a Rat Model of Non-Bacterial Prostatic Inflammation. Prostate 77:803-811 |
