Inhibitory effects of the gastrin receptor antagonist CR2093 on basal, gastrin-stimulated and growth factor-stimulated growth of the rat pancreatic cell line AR42J

Abstract

AR42J, a rat pancreatic cell line expressing receptors for both gastrin and epidermal growth factor (EGF), has been used to examine the effect of the gastrin receptor antagonist CR2093 on basal, gastrin-17 (G17), EGF and transforming growth factor (TGF)-α stimulated growth In vitro. In serum-free conditions, CR2093 reduced the basal growth of AR42J at a concentration known to displace physiological levels of G17 from gastrin receptors and this effect was reversed by G17 at 1 x 10 -9 M. Alone, G17 had little effect on growth, but EGF and TGF-α stimulated growth to 181 and 176% of control values, respectively, and marked synergy was observed when G17 was used In combination with both EGF (212%) and TGF-α (259%). When CR2093 was added, the synerglstlc effects of the G17/EGF and G17/TGF-α combinations were reduced to basal levels. In addition, CR2093 Inhibited the growth stimulation Induced by EGF and TGF-α alone. When the ability of CR2093 to bind to EGF receptors was assessed In a llgand binding assay, It was found that the antagonist displaced up to 23% of labeled EGF. Thus CR2093 has potent inhibitory effects on the basal growth of AR42J which can be reversed by G17. It can also Inhibit type 1 growth factor-stimulated growth, but although this action may In part be related to the antagonist's ability to Inhibit binding to the EGF receptor, other mechanisms may be Involved.