New insights into the RNA-based mechanism of action of the anticancer drug 5'-fluorouracil in eukaryotic cells

PLoS One. 2013 Nov 1;8(11):e78172. doi: 10.1371/journal.pone.0078172. eCollection 2013.

Abstract

5-Fluorouracil (5FU) is a chemotherapeutic drug widely used in treating a range of advanced, solid tumours and, in particular, colorectal cancer. Here, we used high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5FU in the eukaryotic model Schizosaccharomyces pombe. This approach combined with real-time quantitative PCR analysis allowed us to detect splicing defects of a significant number of intron-containing mRNA, in addition to identify some rRNA and tRNA processing defects after 5FU treatment. Interestingly, our studies also revealed that 5FU specifically induced the expression of certain genes implicated in the processing of mRNA, tRNA and rRNA precursors, and in the post-transcriptional modification of uracil residues in RNA. The transcription of several tRNA genes was also significantly induced after drug exposure. These transcriptional changes might represent a cellular response mechanism to counteract 5FU damage since deletion strains for some of these up-regulated genes were hypersensitive to 5FU. Moreover, most of these RNA processing genes have human orthologs that participate in conserved pathways, suggesting that they could be novel targets to improve the efficacy of 5FU-based treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology*
  • Fluorouracil / pharmacology*
  • Humans
  • Molecular Sequence Annotation
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA Splicing
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA, Ribosomal / genetics*
  • RNA, Ribosomal / metabolism
  • RNA, Transfer / genetics*
  • RNA, Transfer / metabolism
  • Schizosaccharomyces / drug effects*
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / metabolism
  • Transcription, Genetic
  • Uracil / metabolism

Substances

  • Antimetabolites, Antineoplastic
  • RNA Precursors
  • RNA, Messenger
  • RNA, Ribosomal
  • Uracil
  • RNA, Transfer
  • Fluorouracil

Grant support

This work was supported by the Spanish Ministry of Economy and Competitiveness (BFU2011-23645 to MS and BFU2011-28274 to SM), the CONSOLIDER-INGENIO from the Spanish Ministry of Science and Innovation CSD2007-00015 (MS and SM), the Fundación Mutua Madrileña (MS) and an Institutional Grant from Fundación Ramón Areces to the Centro de Biología Molecular “Severo Ochoa”. Funding for LQ research come from the Spanish Ministry of Economy and Competitiveness (BFU2011-28804); LM was holder of a CONSOLIDER-INGENIO contract. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.