Aberrant expression of fibroblast growth factor receptor-1 in prostate epithelial cells allows induction of promatrilysin expression by fibroblast growth factors.
Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins, and there is evidence that they play a role in tumor cell growth, invasion and metastasis. Matrilysin (MMP-7) is over-expressed in prostate cancer cells and increases prostate cancer cell invasion. Prostate stromal fibroblasts secrete a factor(s), including fibroblast growth factor-1 (FGF-1), which induces promatrilysin expression in the prostate carcinoma cell line LNCaP but not in normal prostate epithelial cells (PrECs). Since FGF-1 is present in the prostate, an altered sensitivity to FGF-1 might explain the up-regulation of matrilysin expression in prostate cancer cells compared to normal prostate epithelium. FGF receptor-1 (FGFR-1) is not normally expressed by normal prostate epithelial cells; however, aberrant expression of this receptor has been reported in prostate cancer cells, including the LNCaP cell line. We hypothesized that aberrant expression of FGFR-1 in PrECs would render them sensitive to induction of promatrilysin expression by recombinant FGF-1. To test this hypothesis, we transiently transfected PrECs with an FGFR-1 expression vector, which resulted in over-expression of FGFR-1 protein in approximately 40% of cells. FGF-1 increased promatrilysin expression in FGFR-1-transfected PrECs 4-fold over mock-transfected cells, and this induction was inhibited by a specific FGFR-1 inhibitor, SU5402, and by co-expression of a dominant negative FGFR-1 protein. Our results demonstrate that aberrant FGFR-1 expression, an epigenetic phenomenon that has been associated with prostate cancer progression, allows induction of promatrilysin expression by FGF-1 in PrECs.
Udayakumar
T S
TS
Department of Radiation Oncology, University of Arizona Health Sciences Center, Tucson, AZ 85724-5024, USA.
Klein
R D
RD
Maliner
M S
MS
Nagle
R B
RB
Bowden
G T
GT
D019281:Dimerization; D004792:Enzyme Precursors / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000737:chemistry; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D011467:Prostate / Q000737:chemistry*; D011758:Pyrroles / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000737:chemistry / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis* / Q000737:chemistry / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C105686:SU 5402; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D008666:Metalloendopeptidases; C099583:promatrilysin