Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance
Gabriel Thérizols, 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, Élise Berthel, Marie Alexandra Albaret, Hichem C. Mertani, Michel Prudhomme, Martin Bertrand, Alexandre David, Jean‐Christophe Saurin, Philippe Bouvet, Éric Rivals, Théophile Ohlmann, Jérôme Guitton, Nicole Dalla Venezia, Julie Pannequin, Frédéric Catez, Jean‐Jacques Diaz
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.