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Fibroblast Growth Factor-2 Inhibits the Maturation of Pro-Insulin-Like Growth Factor-II (Pro-IGF-II) and the Expression of Insulin-Like Growth Factor Binding Protein-2 (IGFBP-2) in the Human Adrenocortical Tumor Cell Line NCI-H295R¹

Laboratoire d’Explorations Fonctionnelles Endocriniennes (N.B., C.G., A.L., R.C., Y.L.), Hôpital Trousseau, 75012 Paris, France, and INSERM Unité U515, Hôpital Saint-Antoine, 75012 Paris, France; INSERM Unité 244 (J.-J.F.), DBMS/BRCE, CEA/Grenoble, 38054 Grenoble cedex 9, France

Address all correspondence and requests for reprints to: Nathalie Boulle, Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 Avenue Arnold NETTER, 75012 Paris, France. E-mail: lab.endoc{at}trs.ap-hop-paris.fr

The IGF system is thought to play a major role in adrenocortical tumorigenesis. In this study, we used the NCI H295R cell line as a model to investigate the effects of fibroblast growth factor-2 (FGF-2), a potent mitogen for normal adrenal cells, on the proliferation and on the expression of the IGF system in cultured adrenocortical tumor cells. Three immunoreactive FGF-2 isoforms of molecular masses 18, 22, and 24 kDa were detected in H295R cell extracts. Recombinant human FGF-2 stimulated the proliferation of adrenocortical tumor cells in a dose- and time-dependent manner, with a maximal effect at a concentration of about 1 ng/ml. Treatment of H295R cells with 10 ng/ml FGF-2 for 7 days had no significant effect on IGF-II messenger RNA levels. However, a marked increase in levels of intracellular IGF-II protein was detected by immunoblotting. In contrast, FGF-2 induced a marked decrease in the amount of IGF-II protein secreted, with the disappearance of mature IGF-II and secretion of higher molecular forms of the growth factor, suggesting modifications of IGF-II processing. Cell cultures in the presence of brefeldin A (1 µg/ml), a specific inhibitor of protein secretion, suggested that FGF-2 did not increase IGF-II synthesis but instead inhibited the secretion of pro-IGF-II from H295R cells, thereby impairing the final steps of IGF-II processing to the mature 7.5-kDa peptide. At the same concentrations, FGF-2 also decreased both IGFBP-2 messenger RNA and secreted protein, which might increase IGF-II bioavailability. No proteolysis of IGFBP-2 was detected in FGF-2-conditioned medium. Altogether, these results indicate that FGF-2 is mitogenic for NCI H295R tumor cells and regulates the expression of both IGF-II and IGFBP-2 in this tumor model. Moreover, this study shows a novel effect of FGF-2, by which this growth factor modulates the processing of pro-IGF-II.

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