Glycine-extended gastrin exerts growth-promoting effects on human colon cancer cells

Background: Since human colon cancers often contain significant quantities of progastrin-processing intermediates, we sought to explore the possibilit y that the biosynthetic precursor of fully processed amidated gastrin, glyc ine-extended gastrin, may exert trophic effects on human colonic cancer cel ls. Materials and Methods: Binding of radiolabeled glycine-extended and amidate d gastrins was assessed on five human cancer cell lines: LoVo, HT 29, HCT 1 16, Cole 320DM, and T 84. Trophic actions of the peptides were assessed by increases in [H-3]thymidine incorporation and cell number. Gastrin expressi on was determined by northern blot and radioimmunoassay. Results: Amidated gastrin did not bind to or stimulate the growth of any of the five cell lines. Ln contrast, saturable binding of radiolabeled glycin e-extended gastrin was seen on LoVo and HT 29 cells that was not inhibited by amidated gastrin (10(-6) M) nor by a gastrin/CCKB receptor antagonist (P D 134308). Glycine-extended gastrin induced a dose-dependent increase in [H -3]thymidine uptake in LoVo (143 +/- 8% versus control at 10(-10) M) and HT 29 (151 +/- 11% versus control at 10(-10) M) cells that was not inhibited by PD 134308 or by a mitogen-activated protein (MAP) or ERK kinase (MEK) in hibitor (PD 98509). Glycine-extended gastrin did stimulate jun-kinase activ ity in LoVo and HT 29 cells. The two cell lines expressed the gastrin gene at low levels and secreted small amounts of amidated gastrin and glycine-ex tended gastrin into the media. Conclusions: Glycine-extended gastrin receptors are present on human colon cancer cells that mediate glycine-extended gastrin's trophic effects via a MEK-independent mechanism. This suggests that glycine-extended gastrin and its novel receptors may play a role in colon cancer cell growth.