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

• Published in: Nature communications Vol. 13; no. 1; pp. 173 - 187
• Main Authors: Therizols, Gabriel, Bash-Imam, Zeina, Panthu, Baptiste, Machon, Christelle, Vincent, Anne, Ripoll, Julie, Nait-Slimane, Sophie, Chalabi-Dchar, Mounira, Gaucherot, Angéline, Garcia, Maxime, Laforêts, Florian, Marcel, Virginie, Boubaker-Vitre, Jihane, Monet, Marie-Ambre, Bouclier, Céline, Vanbelle, Christophe, Souahlia, Guillaume, Berthel, Elise, Albaret, Marie Alexandra, Mertani, Hichem C., Prudhomme, Michel, Bertrand, Martin, David, Alexandre, Saurin, Jean-Christophe, Bouvet, Philippe, Rivals, Eric, Ohlmann, Théophile, Guitton, Jérôme, Dalla Venezia, Nicole, Pannequin, Julie, Catez, Frédéric, Diaz, Jean-Jacques
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 14/19; 14/5; 14/63; 38/91; 5' Untranslated Regions; 5-Fluorouracil; 631/337/1645/2570; 631/337/574; 631/337/574/1789; 631/67/1059/2326; 82/29; Antimetabolites, Antineoplastic - pharmacology; Biochemistry, Molecular Biology; Cancer; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Chemoresistance; Chemotherapy; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA biosynthesis; DNA Replication; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Drug Resistance, Neoplasm - genetics; Drug Tolerance - genetics; Fluorination; Fluorouracil - pharmacology; Genomics; Halogenation; HCT116 Cells; Humanities and Social Sciences; Humans; Immunological tolerance; Insulin-like growth factors; Life Sciences; mRNA; multidisciplinary; Phenotypes; Protein Biosynthesis - drug effects; Receptor, IGF Type 1 - agonists; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Ribosomes; Ribosomes - drug effects; Ribosomes - genetics; Ribosomes - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Ribosomal - genetics; RNA, Ribosomal - metabolism; Science; Science (multidisciplinary); Survival; Translation; Tumor cell lines; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27847-8

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. Different mechanisms have been reported to explain resistance to chemotherapy in cancer. Here, the authors show that the chemotherapeutic drug 5-fluorouracil alters the function of ribosomes to promote pro-survival gene translation leading to chemotherapy resistance.