Regulation of steroidogenesis by insulin-like growth factors (IGFs) in adult human adrenocortical cells: IGF-I and, more potently, IGF-II preferentially enhance androgen biosynthesis through interaction with the IGF-I receptor and IGF-binding proteins

Abstract

Although the effect of insulin-like growth factors (IGFs) in fetal adrenocortical cells has been investigated extensively, the role of the IGF system in the adult human adrenal gland remains unclear. In the present study we investigated the effect of recombinant human IGF-I and IGF-II on cortisol, dehydroepiandrosterone sulfate (DHEA-S) and cAMP synthesis in adult human adrenocortical cells in primary culture. Both IGFs stimulate basal as well as adrenocorticotropin (ACTH)-induced steroid secretion in a time-and dose-dependent fashion. While both IGFs (6·5 nM) induced only a moderate 2-fold increase in basal cortisol output after 48 h, the effect on basal DHEA-S secretion was significantly stronger, with a 2·7-and 3·7-fold stimulation by IGF-I and IGF-II respectively. Similarly, IGF-II enhanced ACTH-induced cortisol and DHEA-S secretion more potently than IGF-I. In doseresponse experiments, the maximum stimulation of ACTH-induced DHEA-S secretion was induced by 1·6 nM IGF-I (2-fold increase) or IGF-II (2·9-fold increase), while the maximum response of cortisol secretion was elicited only at 13 nM IGF-I (2-fold increase) or IGF-II (2·5-fold increase). This resulted in a significant shift of the DHEA-S dose-response curves to the left, indicating a relative selective stimulation of androgen biosynthesis by physiologically low concentrations (0·4-3·2 nM) of IGF-II, and less potently by IGF-I. At all doses tested, the steroidogenic effect of IGF-II was significantly stronger than the effect of IGF-I. Although both IGF receptors are present in adult human adrenocortical cells, the steroidogenic effect of IGF-II is mediated through the IGF-I receptor, since [Arg 54,55 ]IGF-II, which only binds to the IGF-I receptor, was equipotent with native IGF-II, whereas [Leu 27 ]IGF-II, which preferentially binds to the type II IGF receptor, did not show any effect. In addition, [des 1-3 ]IGF-I, which exhibits only minimal binding to IGFBPs, was significantly more potent than native IGF-I in stimulating adrenal steroid biosynthesis, and elicited almost the same maximum stimulatory effect as IGF-II and [des [1][2][3][4][5][6] ]IGF-II. By Western ligand blotting of conditioned medium it was shown that adult human adrenocortical cells secrete various IGF-binding proteins (IGFBPs), which are induced differentially by treatment with ACTH. In conclusion, these results demonstrate that: (1) IGF-II stimulates basal as well as ACTH-induced DHEA-S and cortisol secretion from adult human adrenocortical cells more potently than IGF-I; (2) both IGFs predominantly stimulate androgen biosynthesis; (3) the steroidogenic effect of IGF-I and IGF-II is mediated through interaction with the IGF-I receptor; (4) the different steroidogenic potency of IGF-I and IGF-II might be explained by interaction of these ligands with locally produced IGFBPs. These data indicate that the IGF system plays an important role in the regulation of the differentiated function of adult human adrenocortical cells.

IGF2 increases de novo steroidogenesis in prostate cancer cells

“…Given the similarities in signalling between insulin and IGF2 (Pandini et al 2004), we hypothesized that the increased IGF2 in the tumour microenvironment may accelerate prostatic de novo steroidogenesis. IGF2 has been shown to initiate steroidogenesis in thecal (Spicer & Aad 2007) and adrenocortical cells (Fottner et al 1998). In this study, we observed increased IGF2 transcript in clinical tumour samples, which correlated with progression to castrate resistance in addition to increased expression of the receptors that facilitate IGF2 signalling: IGF1R and INSR.…”

Overexpression of the insulin-like growth factor I receptor in human pheochromocytomas

“…Previous studies by our own group and by others have shown a critical role of the IGF system in either normal adrenocortical cells or in adrenocortical tumors , Boulle et al 1998, Fottner et al 1998. Several authors report the effects of high amounts of IGF-II in human adrenal pheochromocytomas on protein and mRNA levels (Hasselbacher et al 1987, Gelato & Vassalotti 1990) despite unaltered levels of IGF-I.…”

“…Previous studies by our own group and others have shown a critical role for the insulin-like growth factor (IGF) system in either normal adrenocortical cells or adrenocortical tumors , Boulle et al 1998, Fottner et al 1998. In malignant adrenocortical carcinomas, overexpression of IGF peptides (mainly IGF-II), receptors (IGF-IR) and binding proteins (IGFBP-2) has been observed.…”

C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)

“…Both peptides activate growth-promoting signal transduction pathways by interacting with their receptors, and, to some extent, can also bind to their mutual receptors or to hybrid insulin/IGF-I receptors [9,10]. Other common effects include stimulation of sex steroid synthesis [41][42][43][44][45] and inhibition of SHBG production [24,26,46]. The associations of C-peptide and IGF-I with sex-steroid hormones and SHBG appeared to be independent, as the correlation between the peptides was low and mutual adjustment did not change the relationships with sex-steroid hormones.…”