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

Gabriel Therizols, et al.

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25th May 20

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

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. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy. 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. 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.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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