ABSTRACT
PURPOSE: Cellular processes are regulated by signals generated by adhesion receptors and growth factor receptors. IGFbinding protein 1 (IGFBP-1) is a molecule which may affect the both signaling pathways through inactivation of IGF-I (ligand for IGF-IR) and binding to RGD region of integrin receptors. Whether this phenomenon is important in communication between insulin-like growth factor receptor (IGF-IR) and ß1-integrin receptor in regulation of prolidase activity and collagen biosynthesis is the aim of this study. MATERIAL AND METHOD: We studied the effects of IGFBP-1, IGF-I, thrombin (integrin activator), echistatin (disintegrin), phosphatidylinositol 3-kinase inhibitor (LY-294002) and ERK 1/2 inhibitors (PD98059 and UO126) on prolidase activity, collagen biosynthesis and expression of proteins participating in pathways generated by these receptors. RESULTS: Stimulation of ß1-integrin and IGF-I receptors by standard ligands was proved to up-regulate collagen synthesis in cultured fibroblasts. IGFBP-1, similarly as echistatin and studied inhibitors, contributed to down-regulation of ERK1/2, Akt, mTOR expression and up-regulation of NFκB. It was accompanied by parallel decrease in prolidase activity and collagen biosynthesis. CONCLUSION: The data suggest that "cross talk" between IGF-I receptor and integrin receptor may play important role in regulation of prolidase activity and collagen biosynthesis.
Subject(s)
Collagen/biosynthesis , Fibroblasts/metabolism , Receptor Cross-Talk/physiology , Receptor, IGF Type 1/metabolism , Signal Transduction/physiology , Butadienes/pharmacology , Cell Line , Chromones/pharmacology , Dipeptidases/metabolism , Enzyme Inhibitors/pharmacology , Fibroblasts/cytology , Fibroblasts/drug effects , Flavonoids/pharmacology , Humans , Insulin-Like Growth Factor Binding Protein 1/pharmacology , Insulin-Like Growth Factor I/pharmacology , Integrin beta1/pharmacology , Intercellular Signaling Peptides and Proteins , Morpholines/pharmacology , Nitriles/pharmacology , Peptides/pharmacology , Phosphorylation/drug effects , Phosphorylation/physiology , Receptor Cross-Talk/drug effects , Signal Transduction/drug effects , Skin/cytology , Thrombin/pharmacologyABSTRACT
PURPOSE: The aim of our study was to evaluate the impact of metronidazole (MTZ) on cytotoxicity and DNA synthesis in MCF-7 (estrogen receptor positive) and MDA-MB-231 (estrogen receptor negative) breast cancer cell lines. MATERIAL/METHODS: Toxicity of MTZ was determined by MTT test. MCF-7 and MDA-MB-231 cells were incubated with metronidazole used in different concentrations for 24, 48 and 72 hours. The effect of MTZ on DNA synthesis was measured as [3H]-thymidine incorporation. RESULTS: We showed that MTZ in concentration 250 µg/ml significantly increases the growth of MCF-7 cell lines after 24 hours of incubation, but it reduces cell viability in concentrations 1 and 10 µg/ml 72 hours after the drug application. Significant increase of MDA-MB-231 cell viability was obtained in MTZ concentration of 250 µg/ml after 24 and 72 hours. The increase of [3H]-thymidine incorporation in MCF-7 cell line treated with MTZ in concentration 250 µg/ml was statistically significant after 24 hours. Great suppression of cell proliferation was obtained in MDA-MB-231 breast cell line after application of the following concentrations of MTZ: 0.1 µg/ml (after 24 hours) and 0.1, 10, 50, 250 µg/ml (after 72h). CONCLUSIONS: We found that metronidazole exerts different dose- and time- dependent effects on human breast cancer cell lines characterized by presence or absence of estrogen receptors. We suggest that these discrepancies may be influenced by the estrogen signaling.
