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Pré-Publication, Document De Travail Année : 2021

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

Gabriel Therizols
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Zeina Bash-Imam
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Baptiste Panthu
Christelle Machon
Anne Vincent
Sophie Nait-Slimane
  • Fonction : Auteur
Maxime Garcia
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Mounira Chalabi-Dchar
Florian Lafôrets
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Virginie Marcel
Jihane Boubaker-Vitre
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Guillaume Souahlia
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Marie-Alexandra Albaret
Hichem Mertani
Michel Prudhomme
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Martin Bertrand
Jean-Christophe Saurin
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Philippe Bouvet
Théophile Ohlmann
Jérôme Guitton
Julie Pannequin
Frédéric Catez
Jean-Jacques Diaz

Résumé

Abstract 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.

Dates et versions

hal-03365253 , version 1 (05-10-2021)

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Gabriel Therizols, Zeina Bash-Imam, Baptiste Panthu, Christelle Machon, Anne Vincent, et al.. Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance. 2021. ⟨hal-03365253⟩

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