Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Silverchair Information Systems full text link Silverchair Information Systems Free PMC article
Full text links

Actions

.2021 Aug 14;3(3):zcab032.
doi: 10.1093/narcan/zcab032. eCollection 2021 Sep.

A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

Affiliations

A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

Mounira Chalabi-Dchar et al. NAR Cancer..

Abstract

5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.

© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.

PubMed Disclaimer

Figures

Graphical Abstract
Graphical Abstract
5-FU integration in ribosomes contributes to cell plasticity through translational reprogramming.
Figure 1.
Figure 1.
Overview of the uptake and efflux of 5-FU in human cells. Uptake (blue) of 5-FU is controlled by the human equilibrative nucleoside transporters hENT1 and hENT2 and by the organic anionic transporter hOAT2. Efflux (red) of 5-fluorodeoxyuridine monophosphate (5-FdUMP), a 5-FU metabolite, is mediated by the multidrug resistance-associated proteins MRP-5 and MRP-8.
Figure 2.
Figure 2.
Overview of the anabolism and catabolism of 5-FU in human cells. The balance between anabolism and catabolism is crucial for the effect of 5-FU on cells. Catabolism is the most rapid process through which 5-FU is degraded in three steps. Anabolism leads to the production of three active metabolites (green): 5-fluorodeoxyuridine monophosphate (5-FdUMP), 5-fluorodeoxyuridine triphosphate (5-FdUTP) and 5-fluorouridine triphosphate (5-FUTP); 5-FdUrd, 5-fluorodeoxyuridine; 5-FdUDP, 5-fluorodeoxyuridine diphosphate; 5-FUrd, 5-fluorouridine; 5-FUMP, 5-fluorouridine monophosphate; 5-FUDP, 5-fluorouridine diphosphate; 5-FUDP-HexNAc, 5-FUDP-N-acetylhexosamine; 5-FUDP-Hex, 5-FUDP-hexose; DHFU, dihydrofluorouracil; FUPA, α-fluoro-β-ureidopropionic acid; FBAL, α-fluoro-β-alanine; TP, thymidine phosphorylase; TK, thymidine kinase; UMPK, UMP kinase; UDPK, UDP kinase; dUH, dUTP hydrolase; UP, uridine phosphorylase; UK, uridine kinase; OPRT, orotate phosphoribosyltransferase; RNR, ribonucleotide reductase; UDPNAP, UDP-N-acetylhexosamine-pyrophosphorylase; UDPGP, UDP-glucose-pyrophosphorylase; DPD, dihydropyrimidine dehydrogenase; DHP, dihydropyrimidinase; BUP-1, β-ureidopropionase. The structural formulas of 5-FU and its metabolites were drawn using the PubChem database (https://pubchem.ncbi.nlm.nih.gov/edit3/index.html).
Figure 3.
Figure 3.
Overview of all RNA that potentially incorporate 5-FU, with a focus on Ribosome Biogenesis (RiBi). RiBi requires the initial transcription of rDNA genes to a single precursor of ribosomal RNA (pre-rRNA), 47S, in the nucleolus, whereas 5S rRNA is transcribed in the nucleoplasm. 47S is subsequently cleaved in several pre-rRNA to ultimately provide 18S, 5.8S and 28S rRNAs. During this processing step, rRNAs are post-transcriptionally modified by protein-processing complexes including fibrillarin (FBL) complexed with C/D box snoRNAs and DKC1 complexed with H/AHA box snoRNAs, which are responsible for 2′-O-methylation and pseudouridylation modifications, respectively. RiBi also requires the transcription of mRNAs encoding ribosomal proteins (RP, not shown here), which, after being translated in the cytoplasm and imported into the nucleus, are assembled into small pre-40S (18S and 32 RPS) and large pre-60S (5S+5.8S+28S and 47 RPL) ribosomal subunits. The two mature subunits are then exported into the cytoplasm and assembled into mature ribosomes (80S), ready to achieve translation with mRNA and tRNA. The extrinsic RNA epitranscriptome created by 5-FU (red star) enforces the expansion of the DNA-based initial view of the deleterious effect of 5-FU on phenotype.
Figure 4.
Figure 4.
Model showing that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and relapse. 5-FU is generally recognized as a disruptor of DNA metabolism contributing to its cytotoxicity. However, 5-FU is mainly incorporated into RNA. Through its integration in rRNA, the most abundant RNA, 5-FU produces active F-ribosomes which induce translational reprogramming accompanied by an incomplete cytotoxicity. Instead, cell plasticity takes place and will ultimately contribute to relapse.
See this image and copyright information in PMC

References

    1. Rutman R.J., Cantarow A., Paschkis K.E. Studies in 2-acetylaminofluorene carcinogenesis. I. The intracellular distribution of nucleic acids and protein in rat liver. Cancer Res. 1954; 14:111–114. - PubMed
    1. Rutman R.J., Cantarow A., Paschkis K.E. Studies in 2-acetylaminofluorene carcinogenesis. III. The utilization of uracil-2-C14 by preneoplastic rat liver and rat hepatoma. Cancer Res. 1954; 14:119–123. - PubMed
    1. Heidelberger C., Chaudhuri N.K., Danneberg P., Mooren D., Griesbach L., Duschinsky R., Schnitzer R.J., Pleven E., Scheiner J. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature. 1957; 179:663–666. - PubMed
    1. Robertson J., Barr R., Shulman L.N., Forte G.B., Magrini N. Essential medicines for cancer: WHO recommendations and national priorities. Bull. World Health Organ. 2016; 94:735–742. - PMC - PubMed
    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018; 68:394–424. - PubMed

LinkOut - more resources

Full text links
Silverchair Information Systems full text link Silverchair Information Systems Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp