Insulin-like growth factor binding protein-3 inhibits cell adhesion via suppression of integrin β4 expression
Copyright policy )Insulin-like growth factor binding protein-3 inhibits cell adhesion via suppression of integrin β4 expression
We previously reported that IGF binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates angiogenic activities of human head and neck squamous cell carcinoma (HNSCC) cells and human umbilical vein endothelial cells (HUVECs) through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in cell adhesion is largely unknown. We demonstrate here that IGFBP-3 inhibits the adhesion of HNSCC cells and HUVECs to the extracellular matrix (ECM). IGFBP-3 reduced transcription of a variety of integrins, especially integrin β4, and suppressed phosphorylation of focal adhesion kinase (FAK) and Src in these cells through both IGF-dependent and IGF-independent pathways. IGFBP-3 was found to suppress the transcription of c-fos and c-jun and the activity of AP1 transcription factor. The regulatory effect of IGFBP-3 on integrin β4 transcription was attenuated by blocking c-jun and c-fos gene expression via siRNA transfection. Taken together, our data show that IGFBP-3 has IGF-dependent and -independent inhibitory effects on intracellular adhesion signaling in HNSCC and HUVECs through its ability to block c-jun and c-fos transcription and thus AP-1-mediated integrin β4 transcription. Collectively, our data suggest that IGFPB-3 may be an effective cancer therapeutic agent by blocking integrin-mediated adhesive activity of tumor and vascular endothelial cells.
- Inje University Korea (Republic of)
- Seoul National University Korea (Republic of)
- College of Pharmacy Iraq
- SEOUL NATIONAL UNIVERSITY
Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Blotting, Western, Integrin beta4, Gene Expression, Recombinant Proteins, Transcription Factor AP-1, Insulin-Like Growth Factor Binding Protein 3, Head and Neck Neoplasms, Cell Line, Tumor, Carcinoma, Squamous Cell, Cell Adhesion, Human Umbilical Vein Endothelial Cells, Humans, RNA Interference, Insulin-Like Growth Factor I, Cells, Cultured, Oligonucleotide Array Sequence Analysis
Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Blotting, Western, Integrin beta4, Gene Expression, Recombinant Proteins, Transcription Factor AP-1, Insulin-Like Growth Factor Binding Protein 3, Head and Neck Neoplasms, Cell Line, Tumor, Carcinoma, Squamous Cell, Cell Adhesion, Human Umbilical Vein Endothelial Cells, Humans, RNA Interference, Insulin-Like Growth Factor I, Cells, Cultured, Oligonucleotide Array Sequence Analysis
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