Fibroblast Growth Factor-1 Induced Promatrilysin Expression Through the Activation of Extracellular-regulated Kinases and STAT3

Abstract

The MMP, matrilysin. (20MMP-7), has been shown to be overexpressed in prostate cancer cells and to increase prostate cancer cell invasion. Prostate stromal fibroblasts secrete factor(s), including fibroblast growth factor-1. (20FGF-1) that induces promatrilysin expression in LNCaP cells. In the present study, we investigated the signal transduction pathway involved in the FGF-1-induced expression of promatrilysin. FGF-1 treatment significantly increased the activation of extracellular signal-regulated kinases 1 and 2. (20ERK1 and ERK2). This induction was time-dependent and was sustained until 24 hours after treatment. Treating the cells with MEK1/2 inhibitor. (20PD98059) eliminated ERK activation completely and blocked FGF-1-mediated induction of promatrilysin expression. Transient transfection studies with human matrilysin promoter resulted in a four-to-five-fold increase in reporter luciferase enzyme activity that was blocked by the MEK1/2 inhibitor. (20PD98059). Serine phosphorylation of signal transducer and activator of transcription 3. (20STAT3) was observed after FGF-1 treatment and pretreatment with 20 µM PD98059 abolished STAT3 phosphorylation. Transient transfection with dominant negative STAT3 inhibited FGF-1-induced transactivation of the matrilysin promoter indicating that STAT3 plays an important role in FGF-1-induced matrilysin expression. We propose that the FGF-1-induced signaling pathway that leads to promatrilysin expression is ERK-dependent and leads to phosphorylation of Ser-727 on STAT3, phosphorylated STAT3, then binds and transactivates the matrilysin promoter. Our results demonstrate that ERK-MAP kinase and transcription factor STAT3 are important components of FGF-1-mediated signaling, which induce promatrilysin expression in LNCaP cells.

Keywords

• matrilysin
• prostate
• STAT3
• FGF-1
• LNCaP