IGF-binding protein-6 is involved in growth inhibition in SH-SY5Y human neuroblastoma cells: its production is both IGF- and cell density-dependent.
The IGF system is involved in the growth and differentiation of neuroblastoma cells, but the precise roles played by the IGF-binding proteins (IGFBPs) remain unknown. We have examined the expression and functions of IGFBPs produced by the neuroblastoma cell line, SH-SY5Y, in the presence of: insulin, IGF-I, IGF-II, des(1-3)IGF-I (an IGF-I analogue with weak affinity for IGFBPs), acidic fibroblast growth factor, basic fibroblast growth factor, or nerve growth factor. Under basal conditions, SH-SY5Y cells in serum-free medium secreted IGF-II, and traces of IGF-I, IGFBP-2 and IGFBP-4. After 24 h of culture, comparative mitogenic potencies were: des(1-3)IGF-I > IGF-I > IGF-II > insulin. After 48 h, when IGFBP-2 and IGFBP-4 concentrations in the culture media had increased, des(1-3)IGF-I remained the most active, but the activity of insulin now equalled or exceeded that of IGF-I and IGF-II. This suggests a negative feedback mechanism involving partial sequestration of IGF-I and IGF-II by IGFBP-2 and IGFBP-4. At high cell density and with high concentrations of IGF-I, des(1-3)IGF-I (40 ng/ml) or IGF-II (80 ng/ml), the mitogenic activities of the IGFs diminished concomitantly with the appearance in the culture medium of an additional IGFBP identified as IGFBP-6, whose production depended on activation of the type 1 IGF receptor. These findings suggest that IGFBP-6 contributes as an autocrine inhibitor in the regulation of growth by the IGF system in these neuroblastoma cells.
Babajko
S
S
Institut National de la Santé et de la Recherche Médicale, Unité de Recherches sur la Régulation de la Croissance (U.142), Hôpital Saint Antoine, Paris, France.
Leneuve
P
P
Loret
C
C
Binoux
M
M
D015153:Blotting, Western; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D005246:Feedback; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D013002:Somatomedins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007328:Insulin; D018976:Insulin-Like Growth Factor Binding Protein 6; D009414:Nerve Growth Factors; D013002:Somatomedins; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II