Carcinogenesis, Vol 19, 2121-2128, Copyright © 1998 by Oxford University Press
JG Scharf, W Schmidt-Sandte, SA Pahernik, G Ramadori, T Braulke and H Hartmann
The insulin-like growth factors (IGF-I and -II) are structurally related
peptides participating in the regulation of metabolism, growth and cellular
differentiation. In the present study, the human hepatoma cell line PLC was
studied for the expression of individual components of the IGF axis.
Northern blot analysis using IGF-I and -II coding cDNAs failed to detect
IGF-I- or -II-specific transcripts in total RNA from PLC cells.
Biosynthesis of type I and II IGF receptors was demonstrated by northern
blotting and binding studies as well as cross- linking of the respective
radiolabeled ligand. Both IGF-I and -II stimulated [3H]-thymidine
incorporation dose-dependently. The mitogenic activity of exogenously added
IGFs was reduced by the presence of IGF- binding proteins of 24, 30, 34, 41
and 45 kDa in supernatants of PLC cells identified as IGFBP-4, -1, -2 and
-3, respectively, by [125I]IGF- I ligand-, immuno- and northern blotting.
Biosynthesis of IGFBP-3 was stimulated dose-dependently by IGF-I and -II,
while IGFBP-1, -2 and -4 were not affected. The increase of IGFBP-3 in
response to IGF-I and -II was due to a stimulation of IGFBP-3 specific mRNA
as well as to an inhibition of IGFBP-3 endocytosis. Proteolytic activity
for rhIGFBP-3 was detected in media from PLC cells at acidic pH that was
inhibited by the aspartyl protease inhibitor pepstatin A as well as after
immunodepletion of cathepsin D from media of PLC cells. Thus, a role of
cathepsin D for the regulation of IGFBP-3 bioavailability via endocytosis
in acidic prelysosomal compartments was suggested. The susceptibility of
PLC for IGF-I and -II was restricted by their ability to increase the
abundance of inhibitory IGFBPs and to decrease the level of IGF-I receptor
expression. The present data point to the IGF axis as a complex regulatory
system that self limits the mitogenic activity of exogenous IGFs.
ARTICLES
Characterization of the insulin-like growth factor axis in a human hepatoma cell line (PLC)
Department of Medicine, George-August-Universitat, Gottingen, Germany. jscharf@med.uni-goettingen.de
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