Genetic and Pharmacologic Inhibition of eIF4E Reduces Breast Cancer Cell Migration, Invasion, and Metastasis

Abstract

The translation initiation factor eIF4E is an oncogene that is commonly overexpressed in primary breast cancers and metastases. In this article, we report that a pharmacologic inhibitor of eIF4E function, ribavirin, safely and potently suppresses breast tumor formation. Ribavirin administration blocked the growth of primary breast tumors in several murine models and reduced the development of lung metastases in an invasive model. Mechanistically, eIF4E silencing or blockade reduced the invasiveness and metastatic capability of breast cancer cells in a manner associated with decreased activity of matrix metalloproteinase (MMP)-3 and MMP-9. Furthermore, eIF4E silencing or ribavirin treatment suppressed features of epithelial-to-mesenchymal transition, a process crucial for metastasis. Our findings offer a preclinical rationale to explore broadening the clinical evaluation of ribavirin, currently being tested in patients with eIF4E-overexpressing leukemia, as a strategy to treat solid tumors such as metastatic breast cancer. Cancer Res; 75(6); 1102-12. Ó2015 AACR.

Differential Regulation of ZEB1 and EMT by MAPK-Interacting Protein Kinases (MNK) and eIF4E in Pancreatic Cancer

“…Our findings contrast with a recent report demonstrating that targeting eIF4E in breast cancer cells inhibited TGF-β-induced vimentin and Snail expression (44). We show that the effect of eIF4E on ZEB1 levels in PDAC cells is through its effect on miR-200c and miR-141 microRNAs.…”

Glucosamine sulfate suppresses the expression of matrix metalloproteinase-3 in osteosarcoma cells in vitro

“…This O-glycosylation is thought to act in a manner analogous to phosphorylation [20, 21]. In support of these findings, recent clinical studies have demonstrated a close correlation between MMP-3 expression and the development of lung metastases in breast and lung cancers [22, 23]. In our study, which analized the expression of three MMPs, we found that glucosamine sulfate treatment exerted an unexpectedly specific effect.…”

Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas

“…19,20 Here, we show that TEHsp90 controls posttranscriptional dynamics of key mRNA species including those encoding BCL6, MYC, and BCL2 in DH/TH DLBCLs. We identify that eIF4E simultaneously modulates the mRNA export and translation of these genes and that TEHsp90 modulates eIF4E activity.…”