Regulation of insulin-like growth factor 1 binding protein 3 levels by epidermal growth factor and retinoic acid in cervical epithelial cells.
Insulin-like growth factors (IGFs) are important regulators of epithelial cell growth. The mitogenic activity of these factors is influenced by the levels of extracellular IGF binding proteins, including insulin-like growth factor binding protein 3 (IGFBP-3). In the present report we study the effects of epidermal growth factor (EGF) and all-trans-retinoic acid (RA) on IGFBP-3 RNA and protein levels in human papillomavirus-immortalized cervical epithelial cells. Treatment of ECE16-1 cells with 3-20 ng/ml EGF causes a marked reduction in IGFBP-3 levels. In contrast, 1 microM RA increases IGFBP-3 mRNA and protein levels in the presence or absence of 20 ng/ml EGF. The response is concentration dependent with a half-maximal increase observed at 1 nM RA. RA is able to reverse the EGF suppression when added simultaneously or 3 days after initiation of EGF treatment. Conversely, when cells are treated with RA, IGFBP-3 levels increase within 24 h and subsequent addition of EGF is without effect. Thus, the RA-dependent increase in IGFBP-3 levels is dominant over the EGF suppression. The increased IGFBP-3 levels are correlated with RA suppression of proliferation. Similar RA effects on IGFBP-3 mRNA levels were observed in other cervical epithelial cell lines (i.e., ECE16-D1, ECE16-D2, and CaSki). These results suggest that RA may act to inhibit cervical cell growth by increasing IGFBP-3 levels and reducing the extracellular concentration of free insulin-like growth factor I (IGFI) and/or alternatively, IGFBP-3 may inhibit cell growth by direct effects on the cell, independent of IGFI.
Andreatta-Van Leyen
S
S
Department of Physiology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4970.
Hembree
J R
JR
Eckert
R L
RL
D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D007700:Kinetics; D014212:Tretinoin / Q000494:pharmacology*
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D014212:Tretinoin; D004815:Epidermal Growth Factor