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Translation of ODC mRNA and polyamine transport are suppressed in ras-transformed CREF cells by depleting translation
J R Graff1, A De Benedetti, J W Olson
1Department of Microbiology and Immunology, L.P. Markey Cancer Center, University of Kentucky, Lexington 40536, USA.
Abstract:
Rapid tumor growth and metastasis require increased polyamine metabolism, which is coordinately regulated by ornithine decarboxylase (ODC) and the polyamine transporter. Both activities are stimulated by ras signalling and are dependent upon protein biosynthesis. T24ras oncogene expression in rat embryo fibroblasts (CREFT24) induces cellular transformation and malignancy, in part, by stimulating the rate-limiting translation initiation factor, eIF-4E. CREFT24 expressing antisense RNA to eIF-4E (AS4E) have markedly decreased tumor growth rates and metastatic capacity, without altered monolayer growth rates. Herein, we demonstrate that in AS4E, ODC is translationally suppressed resulting in decreased ODC activity. Additionally, exogenous polyamine uptake is suppressed in AS4E cells indicating that AS4E can neither generate nor import the polyamines necessary to support rapid tumor growth. These data provide evidence that eIF-4E is the link between ras-induced malignancy and increased polyamine metabolism and support the hypothesis that eIF-4E plays a pivotal role in mediating ras-induced malignancy.
Insights
Inhibition of eukaryotic initiation factor 4E (eIF-4E) reduces tumor growth and metastasis by suppressing polyamine metabolism. This highlights eIF-4E
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Rapid tumor growth and metastasis necessitate enhanced polyamine metabolism, regulated by ornithine decarboxylase (ODC) and polyamine transporters.
- Ras signaling stimulates ODC and polyamine transporter activity, which are dependent on protein biosynthesis.
- T24ras oncogene expression in rat embryo fibroblasts (CREFT24) induces cellular transformation and malignancy by stimulating the translation initiation factor eIF-4E.
Purpose of the Study:
- To investigate the role of eukaryotic initiation factor 4E (eIF-4E) in mediating ras-induced malignancy and its impact on polyamine metabolism.
- To determine if suppressing eIF-4E affects ornithine decarboxylase (ODC) activity and polyamine uptake in cancer cells.
Main Methods:
- Utilized CREFT24 cells expressing antisense RNA to eIF-4E (AS4E) to reduce eIF-4E levels.
- Assessed tumor growth rates and metastatic capacity in vivo.
- Measured ODC activity and exogenous polyamine uptake in AS4E cells.
Main Results:
- AS4E cells exhibited markedly decreased tumor growth rates and metastatic capacity compared to control CREFT24 cells.
- In AS4E cells, ornithine decarboxylase (ODC) was translationally suppressed, leading to decreased ODC activity.
- Exogenous polyamine uptake was suppressed in AS4E cells, indicating impaired polyamine generation and import.
Conclusions:
- Eukaryotic initiation factor 4E (eIF-4E) acts as a crucial link between ras-induced malignancy and increased polyamine metabolism.
- Suppression of eIF-4E inhibits both the synthesis and uptake of polyamines essential for rapid tumor growth.
- These findings support the pivotal role of eIF-4E in mediating ras-induced malignant progression.