Cyclooxygenase-2 activates EGFR-ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia

COX-2 stimulates the ERK1/2 pathway via PGE2-ADAM-17-catalyzed shedding of TGF-α in testosterone-induced BPH. The results indicate a functional correlation between inflammation and hyperplasia in BPH.

Prostatic inflammation and hyperplasia were assessed by organ weight and histopathology. Inflammatory mediators were measured using ELISA technique. Protein analysis was performed using western blotting and immunohistochemistry. Gene expression analysis was performed using qRT-PCR. Statistical analyses included one-way ANOVA and Tukey's multiple comparison test.

Testosterone-treated rats had a marked increase in COX-2, prostate weight, and index. Moreover, TST-induced COX-2 was inferred from cytoskeletal changes and was attributable to the overexpression of PGE2, NF-κB (p65), and IL-6. COX-2-derived PGE2 increased the activity of ADAM-17, TGF-α, and TNF-α. Consequently, EGFR-ERK1/2 pathway was over-activated, disrupting anti-apoptotic Bcl-2, cyclin D1, and pro-apoptotic Bax. Celecoxib reversed these effects.