title: Insulin-like growth factor binding protein-3 inhibits cell adhesion via suppression of integrin β4 expression.
abstract: 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.
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyungnam, Republic of Korea.|u-Healthcare and Anti-aging Research Center (u-HARC), Inje University, Gimhae, Republic of Korea.|Biohealth Products Research Center (BPRC), Inje University, Gimhae, Republic of Korea.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyungnam, Republic of Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D039663:Integrin beta4 / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D039663:Integrin beta4; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D007334:Insulin-Like Growth Factor I
keywords: AP-1; IGF-1; IGFBP-3; angiogenesis; cell adhesion; integrin