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EIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression.

ABSTRACT: Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5' cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs.

SUBMITTER: Furic L

PROVIDER: S-EPMC2922605 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression.

Furic Luc L Rong Liwei L Larsson Ola O Koumakpayi Ismaël Hervé IH Yoshida Kaori K Brueschke Andrea A Petroulakis Emmanuel E Robichaud Nathaniel N Pollak Michael M Gaboury Louis A LA Pandolfi Pier Paolo PP Saad Fred F Sonenberg Nahum N

Proceedings of the National Academy of Sciences of the United States of America 20100802 32

Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5' cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, ...[more]

PMID: 20679199

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Project description:Interleukin (IL)-35 is a novel member of the IL-12 cytokine family, which exhibits a unique immune regulatory function. Previously, it was demonstrated that IL-35 expression is significantly increased in a wide range of tumor tissues, promoting angiogenesis and inhibiting the anti-tumor immune response. In the present study, the IL-35 protein expression levels were measured in the plasma and tumor tissue of patients with prostate cancer (PCA), and its role was determined in the occurrence and progression of PCA. Plasma IL-35 expression levels were measured using ELISA, and the associations of plasma IL-35 and clinicopathological parameters were analyzed. Receiver operating characteristic curves were plotted to analyze the role of IL-35 as a clinical biomarker for the diagnosis of PCA. Survival curve analysis demonstrated a significant decrease in the survival time in months in patients with PCA and increased expression levels of IL-35 compared with the participants with relatively lower IL-35 protein expression levels. IL-35 expression was detected using immunohistochemical staining of a human PCA tissue microarray. Plasma IL-35 expression levels in the patients with PCA were significantly increased compared with the patients with benign prostatic hyperplasia and the healthy controls. An increase in the plasma concentration of IL-35 was associated with progression of PCA stage and an increase in the Gleason score. Significant differences in AUCs for IL-35 and prostate-specific antigen were observed with regard to the presence of lymph node and distant metastases in patients with PCA. The expression levels of Epstein-barr virus-induced gene 3 (EBI3) and IL-12A (p35; the subunits which together form IL-35) were significantly increased in the tumor tissue compared with the adjacent normal tissue. An association was identified between the Gleason score and the expression of EBI3 and p35. Therefore, increased expression of IL-35 in the plasma and tumor tissues may contribute to the progression and metastasis of PCA, and IL-35 may serve as a novel prognostic biomarker or therapeutic target for the treatment of PCA.

Dataset Information

EIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression.

Publications

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression.

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