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Pancreatic tumours escape from translational control through 4E-BP1 loss

Oncogene volume 33, pages 1367–1374 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by grants from INSERM-Université Paul Sabatier and from La LIGUE (‘Comités de Hautes-Pyrénées et de Lot-et-Garonne’ and ‘Equipes Labellisées’ programs) to SP. Yvan Martineau was a recipient of Fondation de France and FRM post-doctoral fellowships. Rania Azar, David Müller and Charline Lasfargues were recipients of doctoral fellowships from ARC, La Ligue Nationale Contre le Cancer and CFP, respectively. Rodica Anesia was supported by the RITC foundation. We thank Dr Marlène Dufresne, Dr Véronique Gigoux and Mr Pascal Clerc for their help in characterising Pdx1Cre-KrasG12D mice. We thank Professor Nahum Sonenberg for anti-eIF4GI antibody and Dr Philippe Pierre for the anti-puromycin antibody.

Author contributions:YM and RA designed, performed and analysed the experiments, and wrote the report. DM, CL, SK and RAn performed experiments and analysed the data. JP provided reagents. CB and SP designed and analysed experiments, and wrote the report.

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Authors and Affiliations

  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

    Y Martineau, R Azar, D Müller, C Lasfargues, S El Khawand, R Anesia, C Bousquet & S Pyronnet

  2. Department of Clinical Pharmacy, Faculty of Pharmacy, Lebanese University, Hadath, Lebanon

    R Azar

  3. Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada

    J Pelletier

  4. Pôle digestif, Centre Hospitalier Universitaire de Rangueil, Toulouse, France

    S Pyronnet

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  1. Y Martineau
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Correspondence to S Pyronnet.

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Martineau, Y., Azar, R., Müller, D. et al. Pancreatic tumours escape from translational control through 4E-BP1 loss. Oncogene 33, 1367–1374 (2014). https://doi.org/10.1038/onc.2013.100

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