Translation of ODC mRNA and polyamine transport are suppressed in ras-transformed CREF cells by depleting translation initiation factor 4E.
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.
Graff
J R
JR
Department of Microbiology and Immunology, L.P. Markey Cancer Center, University of Kentucky, Lexington 40536, USA.
De Benedetti
A
A
Olson
J W
JW
Tamez
P
P
Casero
R A
RA
Zimmer
S G
SG
D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002461:Cell Line, Transformed; D004622:Embryo, Mammalian; D039561:Eukaryotic Initiation Factor-4E; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D011905:Genes, ras; D009955:Ornithine Decarboxylase / Q000235:genetics* / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000172:deficiency / Q000235:genetics*; D011073:Polyamines / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D015398:Signal Transduction / Q000235:genetics
D039561:Eukaryotic Initiation Factor-4E; D010448:Peptide Initiation Factors; D011073:Polyamines; D012333:RNA, Messenger; D009955:Ornithine Decarboxylase