“Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance”
Within the framework of a collaboration led by the CRCL of Lyon (also the IGF in Montpellier), this work focuses on the molecular and cellular consequences induced in colorectal cancer by the chemotherapy product 5-fluorouracil (5-FU).
This is a fine example of the multidisciplinary aspects of this work with researchers from LIRMM (Julie Ripoll) and INSERM: on the one hand, biology, and on the other, computer science. Advances are only possible thanks to these contributions, to this synergy.
Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance
Nature Communications volume 13, Article number: 173 (2022)
https://doi.org/10.1038/s41467-021-27847-8
5-Fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for cancer treatment. Its efficacy, particularly when combined with other drugs, has been demonstrated for many years. However, the treatment of some patients with these chemotherapies is made difficult because some cancers can escape these treatments. It is therefore necessary to understand the molecular mechanisms responsible for this escape in order to counteract them and further improve their efficacy. Although prescribed as a modulator of DNA replication, 5-FU also interferes in parallel with all RNA production pathways. RNA is a constituent biomolecule of several molecular micro-machines, and in particular ribosomes which are the micro-factories that synthesise proteins. Our laboratories have just made a major discovery by showing that 5-FU integrates into the RNAs constituting the ribosomes, which induces an important modification of their activity. In particular, our study shows that these 5-FU-modified ribosomes unexpectedly support the synthesis of messenger RNAs coding for proteins that allow cancer cells to survive, and thus escape chemotherapy. The identification for the first time of this mechanism of resistance to chemotherapy treatment is important because it opens up possibilities for improving this type of treatment that have been totally unexplored until now.The alteration of the activity of ribosomes that contain 5-FU has been demonstrated, among other things, by bioinformatic analysis of high-throughput sequencing data that targets all the RNAs translated by these ribosomes.