Deregulation of the phosphatidyl inositol trisphosphate kinase/AKT/mammalian target of rapamycin (mTOR) and RAS/mitogen-activated protein kinase (MAPK)/MNK pathways frequently occurs in human prostate carcinomas (PCas) and leads to aberrant modulation of messenger RNA (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. In 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 terminal oligopyrimidine messenger RNAs (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.

Bianchini, A., Loiarro, M., Bielli, P., Busa, R., Paronetto, M., Loreni, F., et al. (2008). Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells. CARCINOGENESIS, 29(12), 2279-2288 [10.1093/carcin/bgn221].

Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells

LORENI, FABRIZIO;GEREMIA, RAFFAELE;SETTE, CLAUDIO
2008-01-01

Abstract

Deregulation of the phosphatidyl inositol trisphosphate kinase/AKT/mammalian target of rapamycin (mTOR) and RAS/mitogen-activated protein kinase (MAPK)/MNK pathways frequently occurs in human prostate carcinomas (PCas) and leads to aberrant modulation of messenger RNA (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. In 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 terminal oligopyrimidine messenger RNAs (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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/16
Settore BIO/11
English
Con Impact Factor ISI
initiation factor 4E; mammalian target of rapamycin; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase inhibitor; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; protein kinase B; rapamycin; article; cell cycle arrest; cell cycle progression; cell proliferation; cell strain LNCaP; cellular stress response; controlled study; feedback system; human; human cell; priority journal; prostate cancer; protein expression; protein phosphorylation; protein synthesis; ribosome; terminal oligopyrimidine tract; translation initiation; translation regulation; Adenosine Triphosphatases; Blotting, Western; Cation Transport Proteins; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Eukaryotic Initiation Factor-4E; Humans; Male; Mitogen-Activated Protein Kinases; Phosphorylation; Polyribosomes; Prostatic Neoplasms; Protein Array Analysis; Protein Biosynthesis; Protein Kinases; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sirolimus; Tumor Markers, Biological
Bianchini, A., Loiarro, M., Bielli, P., Busa, R., Paronetto, M., Loreni, F., et al. (2008). Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells. CARCINOGENESIS, 29(12), 2279-2288 [10.1093/carcin/bgn221].
Bianchini, A; Loiarro, M; Bielli, P; Busa, R; Paronetto, M; Loreni, F; Geremia, R; Sette, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/27082
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