title: The effects of 5-fluorouracil on the proteome of colon cancer cells.
abstract: The pyrimidine analogue 5-fluorouracil (5FU) is used as a treatment for solid tumors, but its mechanism of action is not fully understood. We have used mass spectrometry to study the mechanism of action of 5FU, and we have measured the effects of this drug on the composition and on the turnover of the proteome of RKO cancer cells. We have identified novel potential targets of 5FU that are affected after very short exposure times. We have also shown that 5FU has a massive effect on the proteins involved in RNA metabolism. After only 1 h of treatment, 5FU causes a post-transcriptional reduction in the abundance of components of the translation machinery (mostly ribosomal proteins), and this reduction is accompanied by a down-regulation of the translational capacity of the cells. Neither rapamycin nor raltitrexed, two drugs that also block cell proliferation, reduce the abundances of ribosomal proteins as 5FU does, which suggests that the down-regulation of ribosomal proteins is coupled to the mechanism of action of 5FU. Some of our observations conflict with previous reports based on RNA quantification. This shows how important it is to complement RNA profiling studies with analyses of drug toxicity at the protein level.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Marin-Vicente
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Lyutvinskiy
authors.forename: Patricia
authors.initials: P
authors.lastname: Romans Fuertes
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zubarev
authors.forename: Neus
authors.initials: N
authors.lastname: Visa
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D014176:Protein Biosynthesis / Q000187:drug effects; D020543:Proteome / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000964:Antimetabolites, Antineoplastic; D020543:Proteome; D012269:Ribosomal Proteins; D005472:Fluorouracil