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 endom etrial epithelial cells. Its action is modulated by the presence of IGF-bin ding proteins (IGFBPs) which are secreted by IGF-I target cells. The partit ion of IGFBPs between cell-associated and soluble form determines the poten tiation or the inhibition of IGF-I action. It is commonly accepted that cel l-associated IGFBPs potentiate the IGF-I action while the soluble form of I GFBPs has an inhibitory effect. In endometrial adenocarcinoma, IGF-I is inv olved 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-1A cell line) to the mitogenic activ ity of IGF-I was dependent on the pie-incubation conditions. This responsiv eness to IGF-I was conditioned by a differential expression of the IGF syst em components (GFBPs and IGF-I receptor) and particularly of the IGFBPs. In deed, the IGF-I-induced proliferation of the HEC-1A cells was attenuated by the presence of cell-associated IGFBPs. Moreover, the IGF-I incubation ind uced a release of IGFBP-3 in the culture media as the consequence of an int eraction between IGF-I and the cell-associated IGFBP-3. This effect was dos e-dependent and was associated with the attenuation of the IGF-I action on cellular proliferation. Thus, IGFBP-3 might be initially expressed as a cel l associated form and then released in the interstitial fluid after a direc t interaction with IGF-I. Therefore, in HEC-1A endometrial adenocarcinoma c ells 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-indu ced cellular proliferation.