Translational control of cell plasticity drives 5-FU tolerance - CRLC Val d'Aurelle - Paul Lamarque
Preprints, Working Papers, ... Year : 2024

Translational control of cell plasticity drives 5-FU tolerance

Anne Vincent
Armelle Choquet
David Bernard
  • Function : Author
  • PersonId : 1062338
Nadine Martin
  • Function : Author
  • PersonId : 1081740
Julie Pannequin

Abstract

All routine clinical treatments for colorectal cancer include 5-fluorouracil (5-FU), which cannot counteract recurrence and metastases formation. As the pyrimidine analog 5-FU can impact multiple pathways including both DNA and RNA metabolism, studying its mode of actions could lead to improved therapies. Using a dedicated reporter system for lineage-tracing and deep translatome profiling we demonstrate that 5-FU causes some colorectal cancer cells to tolerate the drug, due to a durable translational reprogramming that sustains cell plasticity. This period of drug tolerance coincides with specific translational activation of genes coding for proteins with major pro-tumoral functions. We unravel a major unexpected translational overexpression of the pro-inflammatory and pro-tumoral IL-8 cytokine, alongside other anti-apoptotic, senescence-associated secretory phenotype and cancer-related senescence phenotype genes. Given the adverse prognostic implications of elevated IL-8 levels across various cancers, our findings suggest IL-8 targeting could counteract 5-FU resistance.
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Dates and versions

hal-04728612 , version 1 (09-10-2024)

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Mounira Chalabi-Dchar, Olivia Villeronce, Julie Ripoll, Anne Vincent, Tanguy Fenouil, et al.. Translational control of cell plasticity drives 5-FU tolerance. 2024. ⟨hal-04728612⟩
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