Carcinogenesis Advance Access published online on September 22, 2008
Carcinogenesis, doi:10.1093/carcin/bgn221
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Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells
1 Department of Public Health and Cell Biology
2 Department of Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy and Fondazione Santa Lucia
3 Neuroembryology Unit, Via di Fosso del Fiorano 64, 00143 Rome, Italy
Corresponding Author: Claudio Sette, PhD, Dept. Public Health and Cell Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy, Tel. 3906 72596260, FAX 3906 72596268, Email: claudio.sette{at}uniroma2.it
Deregulation of the PI3K/AKT/mTOR and RAS/MAPK/MNK pathways frequently occurs in human prostate carcinomas (PCas) and leads to aberrant modulation of mRNA translation. We have investigated the relative contribution of these pathways to translational regulation and proliferation of PCa cells. MNK-dependent phosphorylation of eIF4E is elevated in DU145 cells, which have low basal levels of AKT/mTOR activity due to the expression of the tumor suppressor PTEN. By contrast, eIF4E phosphorylation is low in PC3 and LNCaP cells with mutated PTEN and constitutively active AKT/mTOR pathway, but it can be strongly induced through inhibition of mTOR activity by rapamycin or serum depletion. Remarkably, we found that inhibition of MNKs strongly reduced the polysomal recruitment of TOP mRNAs, which are known targets of mTOR-dependent translational control. Pull-down assays of the eIF4F complex indicated that translation initiation was differently affected by inhibition of MNKs and mTOR. In addition, concomitant treatment with MNK-inhibitor and rapamycin exerted additive effects on polysomal recruitment of TOP mRNAs and protein synthesis. The MNK-inhibitor was more effective than rapamycin in blocking proliferation of PTEN-expressing cells, whereas combination of the two inhibitors suppressed cell cycle progression in both cell lines. Microarray analysis showed that MNK affected translation of mRNAs involved in cell cycle progression. Thus, our results indicate that a balance between the activity of the AKT/mTOR and the MAPK/MNK pathway in PCa cells maintains a defined translational level of specific mRNAs required for ribosome biogenesis, cell proliferation and stress response and might confer to these cells the ability to overcome negative insults.
Key Words: mTOR • MNK • translational regulation • signal transduction • prostate cancer
Received July 22, 2008; revised September 5, 2008; accepted September 12, 2008.
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