MODULATION OF INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) RECEPTORS AND MEMBRANE-ASSOCIATED IGF-BINDING PROTEINS IN ENDOMETRIAL CANCER-CELLS BY ESTRADIOL

Insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins (IGFBPs) were examined in Ishikawa endometrial c ancer cells. Our findings suggest that about 95% of [I-125]IGF-I is bo und to membrane-associated IGFBPs rather than to IGF-I receptors. Spec ifically, [I-125]IGF-I binding to cell membranes could be completely d isplaced by cold IGF-I or IGF-II, but not by insulin, suggesting that binding was primarily due to IGFBPs. This was confirmed by using [I-12 5]des-(1-3)IGF-I as the ligand. Des-(1-3)IGF-I binds with high affinit y to IGF-I receptors, but with markedly lower affinity to IGFBPs. [I-1 25]Des-(1-3)IGF-I bound to Ishikawa cells was displaced by IGF-I, IGF- II, and insulin. These results suggest that measuring IGF-I receptor l evels using labeled IGF-I may be misleading. Accordingly, we evaluated the differential binding of [I-125]IGF-I and [I-125]des-(1-3)IGF-I to study the involvement of the IGF system in the stimulation of Ishikaw a cell growth by estradiol. IGF-I stimulates Ishikawa cell proliferati on, but at low concentrations, and this stimulation is largely depende nt on the presence of estradiol. Estradiol caused a 2.5-fold increase in IGF-I receptor levels. Moreover, estradiol reduced soluble IGFBP le vels, presumably increasing the availability of IGFs for their recepto rs. This elevation in IGF-I receptor levels and the decrease in IGFBP levels were accompanied by a 3.5-fold increase in IGF-I receptor messe nger RNA and a 2.5-fold decrease in IGFBP messenger RNAs. These experi ments suggest that estradiol sensitizes endometrial cancer cells to th e effects of IGFs by simultaneously elevating receptor levels and decr easing (potentially inhibitory) IGFBP levels.