An RNA Damage Response Network Mediates the Lethality of 5-FU in Clinically Relevant Tumor Types
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Le résumé fourni par la source
5-fluorouracil (5-FU) is a successful and broadly used anti-cancer therapeutic. A major mechanism of action of 5-FU is thought to be through thymidylate synthase (TYMS) inhibition resulting in dTTP depletion and activation of the DNA damage response. This suggests that 5-FU should synergize with other DNA damaging agents. However, we found that combinations of 5-FU and oxaliplatin or irinotecan failed to display any evidence of synergy in clinical trials, and resulted in sub-additive killing in a panel of colorectal cancer (CRC) cell lines. In seeking to understand this antagonism, we unexpectedly found that an RNA damage response during ribosome biogenesis dominates the drug's efficacy in tumor types for which 5-FU shows clinical benefit. 5-FU has an inherent bias for RNA incorporation, and blocking this greatly reduced drug-induced lethality, indicating that accumulation of damaged RNA is more deleterious than the lack of new RNA synthesis. Using 5-FU metabolites that specifically incorporate into either RNA or DNA revealed that CRC cell lines and patient-derived colorectal cancer organoids are inherently more sensitive to RNA damage. This difference held true in cell lines from other tissues in which 5-FU has shown clinical utility, whereas cell lines from tumor tissues that lack clinical 5-FU responsiveness typically showed greater sensitivity to the drug's DNA damage effects. Analysis of changes in the phosphoproteome and ubiquitinome shows RNA damage triggers the selective ubiquitination of multiple ribosomal proteins leading to autophagy-dependent rRNA catabolism and proteasome-dependent degradation of ubiquitinated ribosome proteins. Further, RNA damage response to 5-FU is selectively enhanced by compounds that promote ribosome biogenesis, such as KDM2A inhibitors. These results demonstrate the presence of a strong RNA damage response linked to apoptotic cell death, with clear utility of combinatorially targeting this response in cancer therapy.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- An RNA Damage Response Network Mediates the Lethality of 5-FU in Clinically Relevant Tumor Types
- Date Crossref
- 29/04/2023
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Massachusetts Institute of Technology Department of Biological Engineering pays non établi dans la noticeUniversité ou école supérieure
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National Institutes of Health pays non établi dans la noticeOrganisme public
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National Cancer Institute Surgical Oncology Program pays non établi dans la noticeOrganisme public
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University of North Carolina at Chapel Hill UNC Lineberger Comprehensive Cancer Center pays non établi dans la noticeUniversité ou école supérieure
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Dana-Farber Cancer Institute Department of Medical Oncology pays non établi dans la noticeStructure de recherche
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Beth Israel Deaconess Medical Center pays non établi dans la noticeÉtablissement de santé
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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David H. Koch Institute for Integrative Cancer Research pays non établi dans la noticeStructure de recherche
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Genentech Biotechnology company pays non établi dans la noticeEntreprise
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Beth Israel Medical Deaconess Medical Center Department of Surgery pays non établi dans la noticeÉtablissement de santé
Department of Biological Engineering — Massachusetts Institute of Technology, National Institutes of Health et Surgical Oncology Program — National Cancer Institute, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.