L. Dagostino et al., MODULATION OF CACO-2 CELL-GROWTH AND POLYAMINE METABOLISM BY PENTAGASTRIN AND GASTRIN ANTAGONISTS, The Cancer journal, 7(1), 1994, pp. 32-38
Background: human colon cancer cells have been found to express gastri
n receptors and a role for gastrin in the growth of colon cancer has b
een postulated. Both mouse colon cancers and colon carcinoma cell line
s are stimulated to grow by gastrin. In the present study we investiga
ted the effects of pentagastrin and the gastrin receptor antagonists p
roglumide, benzotript and CR 2093 on the growth and polyamine metaboli
sm of the human colon carcinoma cells Caco-2 which, after a phase of a
ctive replication, spontaneously differentiate into mature enterocytes
. Methods: cells were grown in Dulbecco's Modified Eagle's medium supp
lemented with 10% fetal calf serum or in serum- free medium containing
pentagastrin and/or proglumide, benzotript or CR 2093. Cell growth wa
s assessed by hemocytometric counting. After treatment, thymidine labe
ling index, ornithine decarboxylase activity and putrescine uptake wer
e evaluated at different time-points. Results: pentagastrin markedly i
ncreased the rate of cell growth and the number of cells in S phase as
well as ornithine decarboxylase activity and putrescine uptake. These
effects were all prevented by the gastrin receptor antagonists, which
reduced the rate of cell growth also in cells not stimulated by the h
ormone. Difluoromethylornithine, a specific and irreversible inhibitor
of ornithine decarboxylase, prevented the proliferative stimulus of p
entagastrin, its effect being abolished by putrescine. Pentagastrin an
d the gastrin receptor antagonists had no effect on differentiated Cac
o-2 cells. Conclusions: pentagastrin stimulates the growth of Caco-2 c
ells by increasing intracellular polyamine concentration through both
enhanced synthesis and increased uptake; the gastrin receptor antagoni
sts prevent these effects. The reduction of the rate of cell growth in
duced by proglumide, benzotript and CR 2093 observed even in cells not
stimulated by pentagastrin may suggest an autocrine production of gas
trin or gastrin-like peptides by Caco-2 cells.