Translational control of pancreatic carcinogenesis


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St├ęphane Pyronnet1
1INSERM U1037, Toulouse, France

Abstract

In the exocrine pancreas, the synthesis of digestive enzymes is controlled by the mRNA cap-binding protein eIF4E. The pancreas is consistently the organ that expresses the eIF4E regulatory protein 4E-BP1 the most. Following food intake, hyperphosphorylation of 4E-BP1 due to mTOR activation releases eIF4E which can then interact with the scaffolding protein eIF4G to form productive cap-binding complexes. Since eIF4G serves as a docking site for the eIF4E-kinase Mnk1, 4E-BP1 hyperphosphorylation and consequently eIF4E-eIF4G interaction is thought to facilitate eIF4E phosphorylation. In addition to its role in protein synthesis, it has recently been shown that eIF4E phosphorylation is critical for cell transformation. The eIF4E-kinase Mnk1 is directly activated by the MAPKs, which are themselves downstream of ras, a proto-oncogene mutated in more than 90% of pancreatic ductal adenocarcinoma (PDAC). Herein we report that 4E-BP1 is no longer expressed in human PDAC, partly due to the loss of function of the transcription factor Smad4 (also termed Deleted in Pancreatic Cancer locus 4 or DPC-4). 4E-BP1 shut-off is also observed in a mouse genetic model of PDAC which is based on a pancreas-specific mutation of ras. 4E-BP1 shut-off and consequently Mnk1 positioning next to eIF4E, together with ras-dependent activation of Mnk1 leads to constitutive phosphorylation of eIF4E. These observations are correlated with an increase in the synthesis of proteins that are critical for cell transformation and tumor malignancy, including cyclin D1, MMP-3 and MMP-9. Thus, these data show a strong defect in the translational control of gene expression in PDAC. They also suggest that the absence of 4E-BP1, one critical target of mTOR, may explain the lack of efficiency of mTOR inhibitors in the treatment of PDAC, and provide a rationale for the use of pharmacological compounds that mimic 4E-BP1 function or inhibit MnK1 activity.