Activation of eIF4E is increased dramatically in advanced prostate cancer and is inversely related to patient survival.

4063 eIF4E is the rate-limiting translation initiation factor governing the delivery of mRNA to ribosomes. eIF4E function is commonly enhanced in human and experimental cancers as a consequence of increased eIF4E expression or enhanced phosphorylation of the inhibitory eIF4E binding protein, 4EBP. Elevated eIF4E function preferentially enhances the translation of numerous potent growth and survival factors (e.g. c-myc, ODC, Cyclin D1). Accordingly, in experimental cancer models, eIF4E overexpression induces cellular transformation, tumorigenicity, invasion, metastasis and chemoresistance whereas eIF4E reduction can suppress malignancy. Increased eIF4E function has been demonstrated in human lymphomas and breast, head and neck, colon and bladder cancers. Moreover, eIF4E expression is consistently upregulated in metastases from numerous solid tumor types. Herein, we show for the first time that eIF4E function is elevated in human and experimental prostate cancers. In experimental prostate cancer models, eIF4E expression is increased specifically in hormone-refractory prostate cancer cells. In LNAI derivatives of LNCaP, 4EBP1 expression is reduced and the protein is hyperphosphorylated- a consequence of enhanced AKT signaling in LNAI cells. In hormone-refractory CWR22R xenograft tumors, the expression of eIF4E is increased relative to that in hormone- sensitive CWR22 tumors. In TRAMP transgenic tumors, eIF4E expression is also dramatically upregulated. Importantly, we also show that eIF4E function is elevated in human prostate cancer tissues. In a series of 140 prostate tissues, we show by immunohistochemistry that the levels of eIF4E and p4EBP1ser65 are substantially elevated in patients with advanced disease (≥ Gleason 7) (p