title: Insulin-like growth factor (IGF) I down-regulates type 1 IGF receptor (IGF 1R) and reduces the IGF I response in A549 non-small-cell lung cancer and Saos-2/B-10 osteoblastic osteosarcoma cells.
abstract: The insulin-like growth factor type 1 receptor (IGF 1R) mediates the acute metabolic effects of IGF I as well as IGF I-stimulated cell proliferation and protection from apoptosis. IGF binding proteins (IGFBPs) can modulate these responses. We, therefore, investigated whether intrinsic IGFBPs interfere with IGF I-induced regulation of IGF 1R expression and with the biological response to IGF I in two human tumor cell lines, the non-small-cell lung cancer cell line A549 and the osteoblastic osteosarcoma cell line Saos-2/B-10. We compared the growth rates, IGFBP production, IGF I binding characteristics, IGF 1R protein and mRNA levels, and the acute IGF I response (stimulation of glycogen synthesis) after pretreatment of the cells in serum-free medium with or without added IGF I or medium supplemented with 5% fetal calf serum (FCS). In contrast to A549 cells, which produce IGF I and significant amounts of IGFBPs, survival and proliferation of Saos-2/B-10 cells, which do not produce IGF I or significant amounts of IGFBPs, depended on the addition of exogenous IGF I. IGF I increased the concentration of IGFBP-2 and -3 and decreased the concentration of IGFBP-4 in the medium of A549 cells. As compared to FCS, IGF I pretreatment in both cell lines decreased the number of specific IGF I binding sites, down-regulated total and membrane IGF 1R protein, and largely reduced or abolished the acute IGF I response without affecting IGF 1R mRNA levels. The data suggest that the IGF 1R protein of the two cell lines is translationally and/or posttranslationally down-regulated by its ligand in the presence and in the absence of locally produced IGFBPs and that the cell lines have retained this negative feedback to counteract IGF I stimulation.
authors.affiliation: Division of Endocrinology and Diabetes, University Hospital Zurich, Zurich, CH-8091, Switzerland.
authors.forename: K T
authors.initials: KT
authors.lastname: Bostedt
authors.forename: C
authors.initials: C
authors.lastname: Schmid
authors.forename: C
authors.initials: C
authors.lastname: Ghirlanda-Keller
authors.forename: R
authors.initials: R
authors.lastname: Olie
authors.forename: K H
authors.initials: KH
authors.lastname: Winterhalter
authors.forename: J
authors.initials: J
authors.lastname: Zapf
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001798:Blood Proteins / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D017077:Culture Media, Conditioned; D018969:Insulin-Like Growth Factor Binding Proteins; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D006003:Glycogen; D017526:Receptor, IGF Type 1; D005947:Glucose