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Regulation of insulin‐like growth factor 1 binding protein 3 levels by epidermal growth factor and retinoic acid in cervical epithelial cells

1994; Wiley; Volume: 160; Issue: 2 Linguagem: Inglês

10.1002/jcp.1041600208

1097-4652

Sheila Andreatta‐Van Leyen, J R Hembree, Richard L. Eckert,

Cancer, Hypoxia, and Metabolism

Abstract 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 μM 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. © 1994 Wiley‐Liss, Inc.