5-Fluorouracil affects assembly of stress granules based on RNA incorporation

Nucleic Acids Res. 2014 Jun;42(10):6436-47. doi: 10.1093/nar/gku264. Epub 2014 Apr 11.


The antimetabolite 5-fluorouracil is a widely used chemotherapeutic for the treatment of several solid cancers. However, resistance to 5-fluorouracil remains a major drawback in its clinical use. In this study we report that treatment of HeLa cells with 5-fluorouracil resulted in de novo assembly of stress granules. Moreover, we revealed that stress granule assembly under stress conditions as well as disassembly is altered in cells treated with 5-fluorouracil. Notably, we discovered that RACK1, a protein mediating cell survival and apoptosis, is a component of 5-fluorouracil-induced stress granules. To explore the mode of action of 5-fluorouracil accountable for de novo stress granule assembly, we analyzed 5-fluorouracil metabolites and noticed that stress granule assembly is caused by RNA, not DNA incorporating 5-fluorouracil metabolites. Interestingly, we observed that other RNA incorporating drugs also cause assembly of stress granules. Thus, our results suggest that incorporation of chemotherapeutics into RNA may result in stress granule assembly with potential significance in chemoresistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / pharmacology*
  • Azacitidine / metabolism
  • Cell Line
  • DNA / metabolism
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fluorouracil / metabolism
  • Fluorouracil / pharmacology*
  • GTP-Binding Proteins / analysis
  • HeLa Cells
  • Humans
  • Neoplasm Proteins / analysis
  • Oxidative Stress
  • RNA / metabolism*
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / analysis
  • Ribonucleoproteins / analysis
  • Ribonucleoproteins / metabolism*
  • Stress, Physiological*
  • Thioguanine / metabolism


  • Antimetabolites, Antineoplastic
  • Eukaryotic Initiation Factor-2
  • Neoplasm Proteins
  • RACK1 protein, human
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • Ribonucleoproteins
  • RNA
  • DNA
  • GTP-Binding Proteins
  • Thioguanine
  • Azacitidine
  • Fluorouracil