New insights into 4E-BP1-regulated translation in cancer progression and metastasis.

Abstract

Remarkable progress has been made highlighting the importance of cap-dependent mRNA translation in cancer progression. 4E-BP1 is a translation initiation repressor by sequestering the mRNA cap-binding protein eIF4E and consequently inhibiting the translation of certain key oncogenic mRNAs encoding proteins for cell proliferation, survival, angiogenesis and malignancy. In most tumors, however, the repressive function of 4E-BP1 is compromised by reduction of its expression or phosphorylation mediated by oncogenic signaling pathways. We recently unveiled that 4E-BP1-regulated cap-dependent translation integrates oncogenic effects of the AKT and ERK signaling pathways on tumor growth and metastatic progression. Mechanistically, we demonstrate that AKT and ERK pathways selectively upregulate survivin expression at the level of translation by convergent activation of the mTORC1/4E-BP1/eIF4E signaling axis. In addition, loss of 4E-BP1 function induces epithelial-mesenchymal transition and increases metastatic capability of cancer cells by translational activation of Snail. Continuous translation of survivin and Snail is important for colorectal cancer progression to metastasis. Herein we discuss our findings concerning deregulation of translation in cancer progression and metastasis and highlight 4E-BP1 as a potential biomarker and therapeutic target.