INHIBITION BY RAPAMYCIN OF ORNITHINE DECARBOXYLASE AND EPITHELIAL-CELL PROLIFERATION IN INTESTINAL IEC-6 CELLS IN CULTURE

1 Induction of the enzyme ornithine decarboxylase (ODC) appears to be controlled primarily at the level of ODC mRNA translation. The immunos uppressant drug, rapamycin, blocked the induction of ODC in response t o serum by roughly 50% but was without effect on transport of putresci ne into the intracellular space. The effect on ODC was specific for th e intracellular signalling pathway leading to activation of p70(S6k), as the immunosuppressant FK 506 was without effect on ODC activity. 2 Exposure of IEC-6 duodenal epithelial cells to rapamycin inhibited cel lular proliferation. The effect of rapamycin was cytostatic in that re moval of the immunosuppressant from the medium resulted in renewed cel l division. Conversely, addition of exogenous putrescine, the product of the ODC catalysed reaction, was unable to reverse the cytostatic ef fects of rapamycin. 3 At a concentration of 10 nM, rapamycin inhibited the induction of ODC by 50%, a level of inhibition which could not be enhanced by exposure cells to 1000 nM rapamycin. This observation sug gests that other intracellular signalling pathways, in addition to the p70(S6k) cascade, might be involved in regulation of translation of O DC mRNA or that rapamycin does not completely inhibit p70(S6k).