Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance
| Autor: | Julie Pannequin, Maxime Garcia, Jean-Jacques Diaz, Gabriel Therizols, Christelle Machon, Florian Laforêts, Jihane Boubaker-Vitre, Michel Prudhomme, Guillaume Souahlia, M. Bertrand, Hichem C. Mertani, Mounira Chalabi-Dchar, Anne Vincent, Nicole Dalla-Venezia, Jérôme Guitton, Zeina Bash-Imam, Frédéric Catez, Philippe Bouvet, Jean-Christophe Saurin, Sophie Nait-Slimane, Marie-Alexandra Albaret, Virginie Marcel, Baptiste Panthu, Théophile Ohlmann |
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| Přispěvatelé: | Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Messenger RNA [SDV]Life Sciences [q-bio] RNA Translation (biology) [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology [SDV.CAN]Life Sciences [q-bio]/Cancer Biology Ribosome 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis Cancer cell Translational regulation Epigenetics Gene 030304 developmental biology |
| Popis: | Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance 1,2. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy 2–4. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways 5–9. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts and human tumours. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5’-untranslated region. As a result, we found that sustained translation of IGF-1R mRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that “man-made” fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance. |
| Databáze: | OpenAIRE |
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