title: Pancreatic tumours escape from translational control through 4E-BP1 loss.
abstract: The mRNA cap-binding protein eIF4E (eukaryotic translation initiation factor 4E) permits ribosome recruitment to capped mRNAs, and its phosphorylated form has an important role in cell transformation. The oncogenic function of eIF4E is, however, antagonised by the hypophosphorylated forms of the inhibitory eIF4E-binding proteins 1 and 2. eIF4E-binding protein 1 and 2 (4E-BP1 and 2) are two major targets of the protein kinase mTOR, and are essential for the antiproliferative effects of mTOR inhibitors. Herein, we report that pancreas expresses specifically and massively 4E-BP1 (4E-BP2 is nearly undetectable). However, 4E-BP1 expression is extinguished in more than half of the human pancreatic ductal adenocarcinomas (PDAC). 4E-BP1 shutoff is recapitulated in a mouse genetic model of PDAC, which is based on a pancreas-specific mutation of Kras, the more frequently mutated oncogene in human pancreatic tumours. 4E-BP1 downregulation enhances eIF4E phosphorylation and facilitates pancreatic cancer cell proliferation in vitro and tumour development in vivo. Furthermore, 4E-BP1 loss combined with the absence of 4E-BP2 renders eIF4E phosphorylation, protein synthesis and cell proliferation resistant to mTOR inhibition. However, proliferation can be better limited by a recently developed compound that mimics the function of 4E-BP1 and 2 independently of mTOR inhibition.
authors.affiliation: Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Martineau
authors.affiliation: 1] Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France [2] Department of Clinical Pharmacy, Faculty of Pharmacy, Lebanese University, Hadath, Lebanon.
authors.forename: R
authors.initials: R
authors.lastname: Azar
authors.affiliation: Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France.
authors.forename: D
authors.initials: D
authors.lastname: Müller
authors.affiliation: Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Lasfargues
authors.affiliation: Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: El Khawand
authors.affiliation: Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France.
authors.forename: R
authors.initials: R
authors.lastname: Anesia
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Bousquet
authors.affiliation: 1] Université de Toulouse, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, INSERM UMR-1037, Toulouse, France [2] Pôle digestif, Centre Hospitalier Universitaire de Rangueil, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Pyronnet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D063646:Carcinogenesis; D018797:Cell Cycle Proteins; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics*; D010766:Phosphorylation; D014176:Protein Biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins