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Down‐regulation of insulin‐like growth factor binding proteins and growth modulation in hepatoma cells by retinoic acid
Author(s) -
Kim DaeGhon,
Lee Daeyeol,
Cho BaikHwan,
You KyungRan,
Kim MiYoung,
Ahn DeukSoo
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510290414
Subject(s) - retinoic acid , growth factor , cell growth , hep g2 , medicine , endocrinology , cell culture , insulin like growth factor , autocrine signalling , insulin like growth factor binding protein , biology , chemistry , microbiology and biotechnology , receptor , biochemistry , genetics
Abstract We observed that all‐ trans ‐retinoic acid (RA) down‐regulated insulin‐like growth factor binding proteins (IGFBPs) in cultured human hepatoma cells (Hep 3B, PLC/PRF/5, and Hep G2); therefore, we characterized the role of this down‐regulation in cell growth. Treatment with 10 μmol/L RA revealed a rapid decrease in IGFBP‐3 within 2 days, and continued treatment with RA for 6 days resulted in a time‐dependent stimulation of Hep 3B cell growth. However, RA treatment decreased IGFBP‐1 in PLC/PRF/5 cells and in Hep G2 cells, and the growth‐stimulatory activity of RA was transient and less prominent, and was finally obliterated in both cell lines. The addition of 5 ng/mL or 50 ng/mL insulin‐like growth factors (IGFs) did not change the growth effects elicited by RA. The addition of IGFBP‐3 (1,000 ng/mL) inhibited the growth of Hep 3B cells and counteracted the growth‐stimulatory activity of RA, but not completely, suggesting that RA has direct growth‐stimulatory activity and that this is enhanced by autocrine down‐regulation of IGFBP‐3. IGFBP‐3 also inhibited the growth of PLC/PRF/5 cells and of Hep G2 cells. Treatment with phosphorylated IGFBP‐1 (1,000 ng/mL) alone or with RA did not affect the growth of PLC/PRF/5 cells or Hep G2 cells. However, addition of dephosphorylated IGFBP‐1, derived from in vivo dephosphorylation of the phosphorylated form, stimulated the growth of both cell lines, independent of interaction with IGF‐I. From these observations, we propose that RA down‐regulates IGFBPs, which in turn causes autocrine modulation of cell growth independent of IGF in hepatoma cells in vitro or in vivo . In addition, RA regulates IGFBPs at the posttranscriptional (Hep 3B cells and Hep G2 cells) or transcriptional level (PLC/PRF/5 cells) in a cell‐specific manner