TRANSLATION OF ODC MESSENGER-RNA AND POLYAMINE TRANSPORT ARE SUPPRESSED IN RAS-TRANSFORMED CREF CELLS BY DEPLETING TRANSLATION INITIATION-FACTOR 4E

Rapid tumor growth and metastasis require increased polyamine metaboli sm, which is coordinately regulated by ornithine decarboxylase (ODC) a nd the polyamine transporter. Both activities are stimulated by ras si gnalling and are dependent upon protein biosynthesis, T24(ras) oncogen e expression in rat embryo fibroblasts (CREFT24) induces cellular tran sformation and malignancy, in part, by stimulating the rate-limiting t ranslation initiation factor, eIF-4E. CREFT24 expressing antisense RNA to eIF-4E (AS4E) have markedly decreased tumor growth rates and metas tatic capacity, without altered monolayer growth rates. Herein, we dem onstrate that in AS4E, ODC is translationally suppressed resulting in decreased ODC activity. Additionally, exogenous polyamine uptake is su ppressed in AS4E cells indicating that AS4E can neither generate nor i mport the polyamines necessary to support rapid tumor growth. These da ta provide evidence that eIF-4E is the link between ras-induced malign ancy and increased polyamine metabolism and support the hypothesis tha t eIF-4E plays a pivotal role in mediating ras-induced malignancy. (C) 1997 Academic Press.