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eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer
David Müller, … , Stéphane Pyronnet, Yvan Martineau
David Müller, … , Stéphane Pyronnet, Yvan Martineau
Published November 1, 2019
Citation Information: JCI Insight. 2019;4(21):e121951. https://doi.org/10.1172/jci.insight.121951.
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Research Article Gastroenterology Oncology Article has an altmetric score of 2

eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2–deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition.

Authors

David Müller, Sauyeun Shin, Théo Goullet de Rugy, Rémi Samain, Romain Baer, Manon Strehaiano, Laia Masvidal-Sanz, Julie Guillermet-Guibert, Christine Jean, Yoshinori Tsukumo, Nahum Sonenberg, Frédéric Marion, Nicolas Guilbaud, Jean-Sébastien Hoffmann, Ola Larsson, Corinne Bousquet, Stéphane Pyronnet, Yvan Martineau

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Figure 3

mTOR inhibition and consequent 4E-BP1 activation impedes DNA replication and DNA repair.

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mTOR inhibition and consequent 4E-BP1 activation impedes DNA replication...
(A) Asynchronous shScramble or sh4E-BP1 MiaPaca-2 cells were incubated with PP242 (5 μM) for 3 hours and labeled with EdU. Nuclear DNA was counterstained by DAPI. (B) The proportions of replicating cells are shown as means and SDs and were generated from at least 3 independent experiments. P values were calculated using 2-way ANOVA (***P < 0.001). (C) Quantitative image-based cytometry (QIBC) single-cell analysis of EdU-labeled cells. Total EdU and DAPI values from A are plotted in a scatter diagram. Percentages indicate the proportion of replicating cells. Quantification of (D) γH2AX-positive and (E) p-53BP1–positive cells in S-phase. Asynchronous cells were pulsed 30 minutes with EdU (10 μM) prior to 2 hours mitomycin C treatment (MMC, 10 μg/ml) and released for 4 hours. Mean γH2AX and p-53BP1 intensity was plotted for every EdU-positive cells in a scatter diagram. P values were calculated using Student’s t test (***P < 0.001). Representative of 3 independent experiments.

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