Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3

Thirupandiyur S. Udayakumar, Mimi Suzanne Stratton, Raymond B. Nagle, George Timothy Bowden

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The MMP, matrilysin (MMP-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 (FGF-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 (ERK1 and ERK2). This induction was time-dependent and was sustained until 24 hours after treatment. Treating the cells with MEK1/2 inhibitor (PD98059) 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 (PD98059). Serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) 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.

Original languageEnglish (US)
Pages (from-to)60-67
Number of pages8
JournalNeoplasia
Volume4
Issue number1
DOIs
StatePublished - Jan 29 2002

Keywords

  • FGF-1
  • LNCaP
  • Matrilysin
  • Prostate
  • STAT3

ASJC Scopus subject areas

  • Cancer Research

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