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 language | English (US) |
|---|---|
| Pages (from-to) | 60-67 |
| Number of pages | 8 |
| Journal | Neoplasia |
| Volume | 4 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2002 |
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Keywords
- FGF-1
- LNCaP
- Matrilysin
- Prostate
- STAT3
ASJC Scopus subject areas
- Cancer Research
Cite this
Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. / Udayakumar, Thirupandiyur S.; Stratton, Mimi Suzanne; Nagle, Raymond B; Bowden, George Timothy.
In: Neoplasia, Vol. 4, No. 1, 2002, p. 60-67.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3
AU - Udayakumar, Thirupandiyur S.
AU - Stratton, Mimi Suzanne
AU - Nagle, Raymond B
AU - Bowden, George Timothy
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - FGF-1
KW - LNCaP
KW - Matrilysin
KW - Prostate
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=0036145712&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036145712&partnerID=8YFLogxK
U2 - 10.1038/sj/neo/7900207
DO - 10.1038/sj/neo/7900207
M3 - Article
C2 - 11922392
AN - SCOPUS:0036145712
VL - 4
SP - 60
EP - 67
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 1
ER -