title: Human equilibrative nucleoside transporter-1 (hENT1) is required for the transcriptomic response of the nucleoside-derived drug 5'-DFUR in breast cancer MCF7 cells.
abstract: Nucleoside analogues are broadly used in cancer treatment. Although nucleoside metabolism is a necessary step in the development of their cytotoxicity, mediated transport across the plasma membrane might be needed for nucleoside-derived drugs to exert their pharmacological action. In this study, we have addressed the question of whether particular plasma membrane transporters contribute to the transcriptomic response associated with nucleoside-derived drug therapy. Firstly, we have characterized the nucleoside transporters responsible for 5'-DFUR uptake into the breast cancer cell line MCF7. 5'-DFUR is the immediate precursor of 5-FU and a metabolite of the orally administered pro-drug capecitabine, currently used in the treatment of breast cancer and other solid tumors. Although 5'-DFUR is a substrate for both plasma membrane equilibrative nucleoside carriers, hENT1 shows higher affinity for this molecule than hENT2. Inhibition of hENT1 function partially protected MCF7 cells from 5'-DFUR-induced cytotoxicity. Secondly, we have used a pharmacogenomic approach to determine how inhibition of hENT1 function contributes to the transcriptomic response associated to 5'-DFUR treatment. Under hENT1 inhibition most of the transcriptional targets of 5'-DFUR action, which were genes associated with apoptosis and cell cycle progression were blocked. This study demonstrates that although 5'-DFUR is substrate for both equilibrative nucleoside carriers, hENT1 function is essential for the full transcriptional response to 5'-DFUR treatment.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Diagonal 645, E-08028 Barcelona, Spain.
authors.forename: Míriam
authors.initials: M
authors.lastname: Molina-Arcas
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: Pedro
authors.initials: P
authors.lastname: Cano-Soldado
authors.forename: Héctor
authors.initials: H
authors.lastname: Hernández-Vargas
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Casado
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.forename: Marçal
authors.initials: M
authors.lastname: Pastor-Anglada
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D005260:Female; D005467:Floxuridine / Q000378:metabolism / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D005467:Floxuridine; C025034:doxifluridine