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We have reported previously mitogenic effects of gastrin on
several immortalized and neoplastic cell lines, including Swiss 3T3
fibroblasts. Receptor subtypes, cholecystokinin (CCK)-A and CCK-B, for
a closely related peptide, cholecystokinin, were recently cloned. These
studies were undertaken to investigate if CCK-A- and CCK-B receptors
were perhaps mediating the mitogenic effects of gastrin on Swiss 3T3
cells. Receptor antagonists that inhibit the biological effects and
binding of peptides to the CCK-A (L-364,718 (L18)) and CCK-B (L-365,260
(L60)) receptors were ineffective toward inhibiting the binding and
proliferative effects of gastrin on Swiss 3T3 cells. Radiolabeled L18
and L60 demonstrated no binding to the cells, indicating that CCK-A and
CCK-B receptors may be absent on Swiss 3T3 cells. Radiolabeled CCK-8,
gastrin, L18, and L60, on the other hand, demonstrated specific binding
to a pancreatic cancer cell line (AR42J cells) (used as a positive
control). In cross-linking studies the molecular mass of the major band
of gastrin receptors (GR) on Swiss 3T3 cells was determined to be
Possible mRNA expression of CCK-A and CCK-B
receptor subtypes by gastrin-responsive rodent intestinal and
fibroblast cell lines (Swiss 3T3, IEC-6, CA) was measured by the
methods of Northern blot analysis and reverse transcriptase-polymerase
chain reaction. mRNA from rat pancreas, AR42J cells, and rat antrum
served as positive controls. We were unable to detect CCK-A and CCK-B
receptor mRNA in the three cell lines by both the methods. The positive
control samples, on the other hand, gave the expected results. Thus the
three gastrin-responsive rodent cell lines examined in this study
lacked CCK-A and CCK-B receptors, but were positive for the gastrin
preferring GR that demonstrated physicochemical and pharmacological
attributes distinct from CCK-A and CCK-B receptors. Since colon cancers
are known to express high concentrations of non-amidated gastrin-like
peptides, a possible autocrine role of glycine extended forms of
gastrin becomes a highly relevant clinical question in the light of the
presence of novel GR on the fibroblast and intestinal cell lines.
Volume 270,
Number 15,
Issue of April 14, pp. 8429-8438, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSENCE OF DETECTABLE CHOLECYSTOKININ (CCK)-A AND CCK-B RECEPTORS
45 kDa. The mitogenic potency of 0.1-1.0 n
M gastrin-like peptides on Swiss 3T3 cells was in the order of
G1-17
G1-17-Gly > G5-17 G5-17-Gly
> G2-17 > CCK-8-Gly G1-17-Lys CCK-8. The
relative binding affinity of the peptides (based on the dose-dependent
inhibition of binding of I-G1-17 to Swiss 3T3
cells) was similar to the relative mitogenic potency of the peptides as
given above. Furthermore, G1-17-Gly was equally effective as
G1-17 in displacing the binding of
I-G1-17 to
the 45-kDa GR from the Swiss 3T3 cells. Based on these studies it
became evident that the novel gastrin preferring GR, expressed by Swiss
3T3 cells, binds and mediates the mitogenic effects of not only the
mature (amidated) forms of gastrin-like peptides but also binds and
meditates the mitogenic effects of glycine-extended forms of
gastrin-like peptides.
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