Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance

Gabriel Therizols, Zeina Bash-Imam, Baptiste Panthu, Christelle Machon, Anne Vincent, Julie Ripoll, Sophie Nait-Slimane, Mounira Chalabi-Dchar, Angéline Gaucherot, Maxime Garcia, Florian Laforêts, Virginie Marcel, Jihane Boubaker-Vitre, Marie-Ambre Monet, Céline Bouclier, Christophe Vanbelle, Guillaume Souahlia, Elise Berthel, Marie Alexandra Albaret, Hichem C. Mertani, Michel Prudhomme, Martin Bertrand, Alexandre David, Jean-Christophe Saurin, Philippe Bouvet, Eric Rivals, Théophile Ohlmann, Jérôme Guitton, Nicole Dalla Venezia, Julie Pannequin, Frédéric Catez () and Jean-Jacques Diaz ()
Additional contact information
Gabriel Therizols: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Zeina Bash-Imam: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Baptiste Panthu: CIRI-Inserm U1111, Ecole Normale Supérieure de Lyon
Christelle Machon: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Anne Vincent: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Julie Ripoll: LIRMM, UMR 5506, University of Montpellier, CNRS
Sophie Nait-Slimane: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Mounira Chalabi-Dchar: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Angéline Gaucherot: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Maxime Garcia: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Florian Laforêts: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Virginie Marcel: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Jihane Boubaker-Vitre: IGF, Univ. Montpellier, CNRS, INSERM
Marie-Ambre Monet: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Céline Bouclier: IGF, Univ. Montpellier, CNRS, INSERM
Christophe Vanbelle: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Guillaume Souahlia: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Elise Berthel: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Marie Alexandra Albaret: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Hichem C. Mertani: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Michel Prudhomme: Department of Digestive Surgery, CHU Nimes, Univ Montpellier
Martin Bertrand: Department of Digestive Surgery, CHU Nimes, Univ Montpellier
Alexandre David: IGF, Univ. Montpellier, CNRS, INSERM
Jean-Christophe Saurin: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Philippe Bouvet: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Eric Rivals: LIRMM, UMR 5506, University of Montpellier, CNRS
Théophile Ohlmann: CIRI-Inserm U1111, Ecole Normale Supérieure de Lyon
Jérôme Guitton: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Nicole Dalla Venezia: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Julie Pannequin: IGF, Univ. Montpellier, CNRS, INSERM
Frédéric Catez: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon
Jean-Jacques Diaz: Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5′-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that “man-made” fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27847-8

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DOI: 10.1038/s41467-021-27847-8

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