The Matrix Metalloproteinase-9 Regulates the Insulin-like Growth Factor-triggered Autocrine Response in DU-145 Carcinoma Cells
| Autor: | Concepción Gómez-Moutón, Leonor Kremer, Rosa Ana Lacalle, Mercedes Llorente, Emilia Mira, Carlos Martínez-A, Santos Mañes |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Matrix metalloproteinase inhibitor
Proteolysis medicine.medical_treatment Biology Biochemistry Receptor IGF Type 1 Mice Insulin-like growth factor Somatomedins Tumor Cells Cultured medicine Animals Humans Collagenases Autocrine signalling Molecular Biology DNA Primers Mice Inbred BALB C Base Sequence medicine.diagnostic_test DNA synthesis Cell growth Autophosphorylation Antibodies Monoclonal 3T3 Cells Cell Biology Cell cycle Molecular biology Insulin-Like Growth Factor Binding Proteins Matrix Metalloproteinase 9 Cell Division |
| Zdroj: | Journal of Biological Chemistry. 274:6935-6945 |
| ISSN: | 0021-9258 |
| Popis: | The androgen-independent human prostate adenocarcinoma cell line DU-145 proliferates in serum-free medium and produces insulin-like growth factors (IGF)-I, IGF-II, and the IGF type-1 receptor (IGF-1R). They also secrete three IGF-binding proteins (IGFBP), IGFBP-2, -3, and -4. Of these, immunoblot analysis revealed selective proteolysis of IGFBP-3, yielding fragments of 31 and 19 kDa. By using an anti-IGF-I-specific monoclonal antibody (mAb), we detect surface receptor-bound IGF-I on serum-starved DU-145 cells, which activates IGF-1R and triggers a mitogenic signal. Incubation of DU-145 cells with blocking anti-IGF-I, anti-IGF-II, or anti-IGF-I plus anti-IGF-II mAb does not, however, inhibit serum-free growth of DU-145. Conversely, anti-IGF-1R mAb and IGFBP-3 inhibit DNA synthesis. IGFBP-3 also modifies the DU-145 cell cycle, decreases p34(cdc2) levels, and IGF-1R autophosphorylation. The antiproliferative IGFBP-3 activity is not IGF-independent, since des-(1-3)IGF-I, which does not bind to IGFBP-3, reverses its inhibitory effect. DU-145 also secretes the matrix metalloproteinase (MMP)-9, which can be detected in both a soluble and a membrane-bound form. Matrix metalloproteinase inhibitors, but not serpins, abrogate DNA synthesis in DU-145 associated with the blocking of IGFBP-3 proteolysis. Overexpression of an antisense cDNA for MMP-9 inhibits 80% of DU-145 cell proliferation that can be reversed by IGF-I in a dose-dependent manner. Inhibition of MMP-9 expression is also associated with a decrease in IGFBP-3 proteolysis and with reduced signaling through the IGF-1R. Our data indicate an IGF autocrine loop operating in DU-145 cells, specifically modulated by IGFBP-3, whose activity may in turn be regulated by IGFBP-3 proteases such as MMP-9. |
| Databáze: | OpenAIRE |
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