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

Bianchini, Andrea; Loiarro, Maria; Bielli, Pamela; Busà, Roberta; Paronetto, Maria Paola; Loreni, Fabrizio; Geremia, Raffaele; Sette, Claudio

doi:10.1093/carcin/bgn221

Cited by 115 publications

(134 citation statements)

References 33 publications

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“…Through an integrated approach using genome-wide ChIP-sequencing and antibody microarrays, we identified MKNK1 to be a YB-1 target that is overexpressed in trastuzumabresistant cell lines. A few recent studies have suggested involvement of MNKs in tumorigenesis (Chrestensen et al, 2007;Wendel et al, 2007;Bianchini et al, 2008;Ueda et al, 2010;Grzmil et al, 2011). Our study is the first to identify a role for MNK1 in drug resistance.…”

Section: Discussionmentioning

confidence: 54%

“…Conversely, in a PTEN-negative lymphoma mouse model, tumorigenesis was suppressed by loss of MNK1/2 (Ueda et al, 2010). MNKs were shown to be more highly phosphorylated in HER2-positive breast cancer as compared with non-tumorigenic cells (Chrestensen et al, 2007), and their inhibition in prostate cancer cells repressed the translation of mRNAs required for cell-cycle progression (Bianchini et al, 2008). Recently, MNK1 was shown to be overexpressed in glioblastoma multiforme primary tumors, and its silencing reduced the proliferation of glioblastoma multiforme cell lines (Grzmil et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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Trastuzumab (Herceptin) resistance is a major obstacle in the treatment of patients with HER2-positive breast cancers. We recently reported that the transcription factor Y-box binding protein-1 (YB-1) leads to acquisition of resistance to trastuzumab in a phosphorylationdependent manner that relies on p90 ribosomal S6 kinase (RSK). To explore how this may occur we compared YB-1 target genes between trastuzumab-sensitive cells (BT474) and those with acquired resistance (HR5 and HR6) using genome-wide chromatin immunoprecipitation sequencing (ChIP-sequencing), which identified 1391 genes uniquely bound by YB-1 in the resistant cell lines. We then examined differences in protein expression and phosphorylation between these cell lines using the Kinexus Kinex antibody microarrays. Cross-referencing these two data sets identified the mitogen-activated protein kinase-interacting kinase (MNK) family as potentially being involved in acquired resistance downstream from YB-1. MNK1 and MNK2 were subsequently shown to be overexpressed in the resistant cell lines; however, only the former was a YB-1 target based on ChIP-PCR and small interfering RNA (siRNA) studies. Importantly, loss of MNK1 expression using siRNA enhanced sensitivity to trastuzumab. Further, MNK1 overexpression was sufficient to confer resistance to trastuzumab in cells that were previously sensitive. We then developed a de novo model of acquired resistance by exposing BT474 cells to trastuzumab for 60 days (BT474LT). Similar to the HR5/HR6 cells, the BT474LT cells had elevated MNK1 levels and were dependent on it for survival. In addition, we demonstrated that RSK phosphorylated MNK1, and that this phosphorylation was required for ability of MNK1 to mediate resistance to trastuzumab. Furthermore, inhibition of RSK with the small molecule BI-D1870 repressed the MNK1-mediated trastuzumab resistance. In conclusion, this unbiased integrated approach identified MNK1 as a player in mediating trastuzumab resistance as a consequence of YB-1 activation, and demonstrated RSK inhibition as a means to overcome recalcitrance to trastuzumab.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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“…The Oncomine database (36) documents that MNK2 is overexpressed 1.5-to 4.4-fold in HR and metastatic prostate tumors (37)(38)(39). Moreover, MNK activity promotes proliferation in prostate cancer cells (40). This is expected to contribute to the increase in eIF4E phosphorylation seen in tumors with high Gleason scores, considering that MNK2 constitutively phosphorylates eIF4E (41).…”

Section: Discussionmentioning

confidence: 99%

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Furic

Liang

Larsson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

466

566

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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. PTEN | translational controlA berrations in the control of mRNA translation initiation have been documented in many tumor types (1-4). Translation initiation is controlled in part by eIF4E, the mRNA 5′ cap-binding protein. eIF4E is a proto-oncogene, inasmuch as its overexpression in immortalized rodent fibroblasts or human epithelial cells causes transformation (5, 6), and in mouse models its overexpression engenders tumor formation (7,8). eIF4E is phosphorylated by the MNK1/2 serine/threonine kinases, which are activated in response to mitogenic and stress signaling downstream of ERK1/2 and p38 MAP kinase, respectively (9, 10). eIF4E phosphorylation at serine 209 by MNK1/2 promotes its transformation activity (11,12). To study the role of eIF4E phosphorylation in tumorigenesis in the whole organism, we generated a knock-in (KI) mouse in which eIF4E serine 209 was mutated to alanine. Here, we show that mouse embryonic fibroblasts (MEFs) isolated from eIF4E S209A/S209A embryos display a marked resistance to oncogene-induced transformation. Furthermore, the mutant mice are viable, but are resistant to development of Pten loss-induced prostate cancer, and this resistance is associated with a decrease in MMP3, CCL2, VEGFC, and BIRC2 proteins. Moreover, eIF4E is highly phosphorylated in hormone-refractory prostate cancer, which correlates with poor clinical outcome. These results demonstrate the importance of eIF4E phosphorylation in tumorigenesis and validate the eIF4E phosphorylation pathway as a potential therapeutic target for cancer. ResultsSer209 Is the Only Phosphorylation Site in eIF4E. To address the role of eIF4E phosphorylation in tumorigenesis, a knock-in (KI) mouse in which serine 209 was replaced by an alanine residue was generated. The strategy and targeting vector construction for the generation, selection, and genotyping of the S209A mice is shown in Fig. S1. The eIF4E S...

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“…Several studies have demonstrated that deletion and/or mutation of the PTEN gene leads to upregulation of the AKT/mTOR pathway, which can lead to increased eIF4E expression. [29][30][31] To confirm this increase in translation machinery activity in our transgenic prostate-specific PTEN À/À mouse model, protein levels of eIF4E, along with other components of translational machinery (such as phosphorylated 4G (p4G) and phosphorylated 4E-BP (p-4EBP), were evaluated and compared between PTEN À/À and control mice ( Figure 7). Our results confirmed that eIF4E along with other p-4G and p-4EBP were upregulated in prostates of PTEN À/À mice.…”

Section: Discussionmentioning

confidence: 93%

Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice

et al. 2011

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In this study, we have taken advantage of over-expression of eukaryotic translation initiation factor 4E (eIF4E) in prostate cancer cells to design a viral-based targeting system of prostate cancer. Three different lengths of 5 0 -untranslated regions (5 0 UTRs) derived from either fibroblast growth factor-2 (FU-FGF2-GW) or ornithine decarboxylase (FU-ODC 149 -GW and FU-ODC 274 -GW) were inserted upstream of enhanced green fluorescent protein (GFP) gene in a lentiviral backbone. Both nonmalignant control (PNT1B and BPH-1) and neoplastic (LNCaP, C4-2, DU145 and PC-3) prostate cell lines were transfected with each plasmid or virus alone, or in the presence of siRNA against eIF4E, and their expression was monitored via GFP protein levels. Two 5 0 UTRs (FU-FGF2-GW and FU-ODC-GW) were selected as being most sensitive to eIF4E status. Lentiviruses containing these sequences were injected directly into the prostates of PTEN À/À (tumor-bearing) and control mice. Immunofluorescence data and western blot analyses determined that a lentivirus containing a 5 0 UTR derived from FGF-2 is the best candidate for directing selective gene expression in the prostate tumors of PTEN À/À mice in vivo. This study demonstrates that judicious selection of a complex 5 0 UTR can enhance selective targeting of viral-based gene therapies for prostate cancer.

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

Cited by 115 publications

References 33 publications

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice

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