Gastrin stimulates expression of protooncogene c-myc through a process involving polyamines in IEC-6 cells

The current study tested the hypothesis that the protooncogene c-myc is involved in the mechanism by which gastrin modulates mucosal cell proliferation. Studies were conducted in the IEC-6 cell line, derived from rat small intestinal crypt cells. Administration of gastrin resulted in the rapid appearance of c-myc mRNA in IEC-6 cells. The increased expression of c-myc began 1 h and peaked 4 h after exposure to gastrin. Maximum increase in c-myc mRNA levels was 7.5-fold the normal value. When cellular protein synthesis was inhibited by addition of cycloheximide, gastrin superinduced c-myc mRNA levels. Gastrin also significantly increased the mRNA levels for ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis, enzyme activity, and intracellular polyamines in IEC-6 cells. Treatment with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, not only completely depleted intracellular polyamines but also significantly prevented the increased expression of c-myc in cells exposed to gastrin. These results show that 1) gastrin stimulates both polyamine biosynthesis and the expression of the c-myc protooncogene, and 2) depletion of intracellular polyamines by DFMO significantly prevented the increased expression of c-myc by gastrin.