Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol

Endocrinology. 1995 Jun;136(6):2531-7. doi: 10.1210/endo.136.6.7750475.


Insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins (IGFBPs) were examined in Ishikawa endometrial cancer cells. Our findings suggest that about 95% of [125I]IGF-I is bound to membrane-associated IGFBPs rather than to IGF-I receptors. Specifically, [125I]IGF-I binding to cell membranes could be completely displaced by cold IGF-I or IGF-II, but not by insulin, suggesting that binding was primarily due to IGFBPs. This was confirmed by using [125I]des-(1-3)IGF-I as the ligand. Des-(1-3) IGF-I binds with high affinity to IGF-I receptors, but with markedly lower affinity to IGFBPs. [125I]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 levels using labeled IGF-I may be misleading. Accordingly, we evaluated the differential binding of [125I]IGF-I and [125I]des-(1-3)IGF-I to study the involvement of the IGF system in the stimulation of Ishikawa cell growth by estradiol. IGF-I stimulates Ishikawa cell proliferation, but at low concentrations, and this stimulation is largely dependent on the presence of estradiol. Estradiol caused a 2.5-fold increase in IGF-I receptor levels. Moreover, estradiol reduced soluble IGFBP levels, presumably increasing the availability of IGFs for their receptors. 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 messenger RNA and a 2.5-fold decrease in IGFBP messenger RNAs. These experiments suggest that estradiol sensitizes endometrial cancer cells to the effects of IGFs by simultaneously elevating receptor levels and decreasing (potentially inhibitory) IGFBP levels.

MeSH terms

  • Binding, Competitive
  • Carrier Proteins / metabolism*
  • Cell Membrane / metabolism
  • Culture Media, Conditioned
  • Drug Synergism
  • Endometrial Neoplasms / metabolism*
  • Estradiol / administration & dosage
  • Estradiol / pharmacology*
  • Female
  • Gene Expression
  • Humans
  • Insulin-Like Growth Factor I / administration & dosage
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / pharmacology
  • Kinetics
  • Peptide Fragments / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / drug effects*
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Somatomedins / metabolism*
  • Tumor Cells, Cultured


  • Carrier Proteins
  • Culture Media, Conditioned
  • Peptide Fragments
  • RNA, Messenger
  • Somatomedins
  • insulin-like growth factor 1, des-(1-3)-
  • Estradiol
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1