Inhibition by rapamycin of ornithine decarboxylase and epithelial cell proliferation in intestinal IEC-6 cells in culture

Abstract

1 Induction of the enzyme ornithine decarboxylase (ODC) appears to be controlled primarily at the level of ODC mRNA translation. The immunosuppressant drug, rapamycin, blocked the induction of ODC in response to serum by roughly 50% but was without e ect on transport of putrescine into the intracellular space. The e ect on ODC was speci®c for the intracellular signalling pathway leading to activation of p70S6k, as the immunosuppressant FK 506 was without e ect on ODC activity. 2 Exposure of IEC-6 duodenal epithelial cells to rapamycin inhibited cellular proliferation. The e ect of rapamycin was cytostatic in that removal of the immunosuppressant from the medium resulted in renewed cell division. Conversely, addition of exogenous putrescine, the product of the ODC catalysed reaction, was unable to reverse the cytostatic e ects 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 suggests that other intracellular signalling pathways, in addition to the p70S6k cascade, might be involved in regulation of translation of ODC mRNA or that rapamycin does not completely inhibit p70S6k. Originally published British Journal of Pharmacology, Vol. 120, No. 4, Feb 1997