Human equilibrative nucleoside transporter-1 (hENT1) is required for the transcriptomic response of the nucleoside-derived drug 5'-DFUR in breast cancer MCF7 cells.
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.
Molina-Arcas
Míriam
M
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Diagonal 645, E-08028 Barcelona, Spain.
Moreno-Bueno
Gema
G
Cano-Soldado
Pedro
P
Hernández-Vargas
Héctor
H
Casado
F Javier
FJ
Palacios
José
J
Pastor-Anglada
Marçal
M
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*
D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D005467:Floxuridine; C025034:doxifluridine