Cell-associated insulin-like growth factor-binding proteins inhibit insulin-like growth factor-I-induced endometrial cancer cell proliferation.
Insulin-like growth factor I (IGF-I) is a peptidic growth factor implicated in the proliferation of a wide variety of cell types, and especially endometrial epithelial cells. Its action is modulated by the presence of IGF-binding proteins (IGFBPs) which are secreted by IGF-I target cells. The partition of IGFBPs between cell-associated and soluble form determines the potentiation or the inhibition of IGF-I action. It is commonly accepted that cell-associated IGFBPs potentiate the IGF-I action while the soluble form of IGFBPs has an inhibitory effect. In endometrial adenocarcinoma, IGF-I is involved in tumoral progression and IGFBPs may be key modulators of the IGF-I-induced cell proliferation. Here we showed that the responsiveness of human endometrial adenocarcinoma cells (HEC-IA cell line) to the mitogenic activity of IGF-I was dependent on the pre-incubation conditions. This responsiveness to IGF-I was conditioned by a differential expression of the IGF system components (IGFBPs and IGF-I receptor) and particularly of the IGFBPs. Indeed, the IGF-I-induced proliferation of the HEC-1A cells was attenuated by the presence of cell-associated IGFBPs. Moreover, the IGF-I incubation induced a release of IGFBP-3 in the culture media as the consequence of an interaction between IGF-I and the cell-associated IGFBP-3. This effect was dose-dependent and was associated with the attenuation of the IGF-I action on cellular proliferation. Thus, IGFBP-3 might be initially expressed as a cell-associated form and then released in the interstitial fluid after a direct interaction with IGF-I. Therefore, in HEC-IA endometrial adenocarcinoma cells responsive to IGF-I, the IGFBP-3 is the main binding protein expressed and both soluble and cell-associated forms act as inhibitors of IGF-I-induced cellular proliferation.
Bermont
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L
Service d'Oncologie et d'Endocrinologie Moleculaires (CHU Besançon and IETG) and CRI 96.01, Besanqon, France.
Fauconnet
S
S
Lamielle
F
F
Adessi
G L
GL
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D001667:Binding, Competitive; D015153:Blotting, Western; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008934:Mitogens / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007457:Iodine Radioisotopes; D008934:Mitogens; D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1