Studying the Role of Eukaryotic Translation Initiation Factor 4E (eIF4E) Phosphorylation by MNK1/2 Kinases in Prostate Cancer Development and Progression

Abstract

Abstract : The mRNA cap-binding protein eukaryotic initiation factor 4E (eIF4E) plays a key role in cancer progression. We have recently shown (Furic et al., 2010) that phosphorylation of eIF4E at Ser209 by the MNK family of kinases promotes prostate cancer progression in a mouse model bearing a tissue-specific conditional PTEN deletion in prostatic epithelia. The mechanism whereby eIF4E phosphorylation promotes prostate cancer development remains unexplored. Genome-wide analysis studies by our group (Furic et al. 2010) had shown that phosphorylation of eIF4E regulated the protein levels of a large number of proteins linked to remodeling of the tissue surrounding the tumor. Of note, the levels of MMP3, a matrix metalloprotease required for epithelia-mesenchymal transition (EMT), is decreased in eIF4E S209A knockin mouse embryo fibroblasts. In a logical continuity of this finding, next we investigated whether eIF4E phosphorylation is a determinant factor in metastatic progression. The ability of eIF4E to promote metastasis in various mouse models and its association with poor prognosis in the clinic is well documented (De Benedetti et al., 2004; Nasr et al., 2013; Pettersson et al., 2011; Graff et al., 2009), but the mechanism by which phospho-eIF4E may promote metastasis is unknown. In this final report, we elucidate a mechanism by which eIF4E phosphorylation drives metastatic progression. Specifically, we show that phosphorylation of eIF4E promotes the translation of Snail2 and MMP3, both key factors in epithelia-mesenchymal transition during metastasis. Our most recent findings yield important information for a better understanding of how phosphorylation of the proto-oncogene eIF4E drives cancer progression.