Expression of the T24ras oncogene induces
malignancy (
tumor growth, invasion and
metastasis) in cloned rat embryo fibroblasts (CREF T24). In CREF T24, the rate of phosphorylation of eukaryotic translation
initiation factor 4E (eIF-4E) is increased, resulting in increased
protein synthesis rates. We have recently shown that reducing the
protein levels of
eIF-4E in CREF T24 (AS4E line) markedly decreases soft-
agar colonization, increases
tumor latency periods and increases
tumor doubling times without significantly altering monolayer growth. In this study, cells with reduced
eIF-4E had delayed and reduced invasiveness and decreased experimental
metastasis. Furthermore, reduced
eIF-4E levels correlated with decreased expression of the
metastasis-associated 92-kDa
collagenase type-IV and exon-6 variants of the CD44 adhesion molecule [CD44(6v)]. Reduced
eIF-4E levels correlated inversely with increased levels of the putative
metastasis-suppressor protein nm23. Cell lines established from AS4E
tumors and lung
metastases exhibited increased levels of
eIF-4E protein and
protein synthesis rates compared to the AS4E line.
Tumor-derived AS4E had the shortened
tumor latency periods of CREF T24 but displayed the slow
tumor-growth rates of AS4E.
Tumor-derived AS4E exhibited the metastatic capacity of CREF T24 controls. Furthermore,
tumor- and lung-nodule-derived AS4E expressed levels of CD44 (6v) and the 92-kDa
collagenase type IV comparable to CREF T24 and displayed reduced levels of nm23 relative to AS4E. These results demonstrate that
eIF-4E is an important effector molecule involved in oncogenic p21ras-induced malignant transformation.