GLYCINE-EXTENDED GASTRIN ACTS AS AN AUTOCRINE GROWTH-FACTOR IN A NONTRANSFORMED COLON CELL-LINE

Background & Aims: The hypothesis that progastrin-derived peptides act as autocrine growth factors for colorectal carcinomas has generated c onsiderable interest. However, the influence of autocrine gastrins on nontumorigenic colonic cells has not been investigated. This study tes ted the above hypothesis in the nontumorigenic, conditionally immortal ized mouse colon cell line YAMC. Methods: The effects of expression of antisense or sense gastrin messenger RNA, treatment with antibodies a gainst progastrin-derived pep tides, or treatment with gastrin recepto r antagonists on YAMC cell proliferation were measured. Results: YAMC clones expressing antisense gastrin messenger RNA had reduced levels o f immunoreactive progastrin-derived peptides and a reduced rate of pro liferation, relative to vector only-transfected cells. Glycine-extende d gastrin(17), but not amidated gastrin(17), reversed the antisense-in duced inhibition of proliferation and stimulated the proliferation of sense-or vector only-transfected cells. YAMC cells bound I-125-glycine -extended gastrin(17), (K-d, 0.36 nmol/L, 1810 sites/cell), but not I- 125-amidated gastrin(17), and binding was unaffected by gastrin recept or antagonists including benzotript. Proliferation of all YAMC clones was partially inhibited either by an antibody selective for glycine-ex tended gastrin or by preincubation with benzotript, and the inhibitory effects were additive. Conclusions: YAMC cells use nonamidated progas trin-derived peptides as autocrine growth factors, partly through bind ing to an extracellular receptor selective for glycine-extended gastri n, and partly through an intracellular mechanism.