title: 5-Fluorouracil affects assembly of stress granules based on RNA incorporation.
abstract: 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.
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany Department of Biology, Chemistry and Pharmacy, Free University Berlin, 14195 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kaehler
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany University Hospital Cologne, Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, 50931 Cologne, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Isensee
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany University Hospital Cologne, Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, 50931 Cologne, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Hucho
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany Dahlem Centre for Genome Research and Medical Systems Biology, 14195 Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany krobitsc@molgen.mpg.de.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Krobitsch
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001374:Azacitidine / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000032:analysis; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000032:analysis; D018384:Oxidative Stress; D012313:RNA / Q000378:metabolism*; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000032:analysis; D012261:Ribonucleoproteins / Q000032:analysis / Q000378:metabolism*; D013312:Stress, Physiological; D013866:Thioguanine / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D015852:Eukaryotic Initiation Factor-2; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D012261:Ribonucleoproteins; D012313:RNA; D004247:DNA; D019204:GTP-Binding Proteins; D013866:Thioguanine; D001374:Azacitidine; D005472:Fluorouracil
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