Cell-cycle-dependent regulation of CNT1, a concentrative nucleoside transporter involved in the uptake of cell-cycle-dependent nucleoside-derived anticancer drugs.
Most nucleoside-derived anticancer drugs are taken up by the high-affinity Na-dependent nucleoside transporter CNT1. Since such drugs are to some extent cell-cycle-dependent in their cytotoxic action, we examined the relationship between CNT1 expression and cell-cycle progression in the rat hepatoma cell line FAO. Cell cultures were synchronized either at late G1 or early S stages by combining mimosin treatment with either previous synchronization or not by serum starvation. Cell-cycle progression was then assessed by measuring [methyl-3H]thymidine incorporation into DNA and monitoring cyclin E and A protein levels. In these conditions, CNT1 protein amounts increase at the G1-S transition. When cells were synchronized using hydroxyurea (HU), which directly interacts with nucleotide metabolism by inhibiting ribonucleotide reductase, CNT1 protein amounts increased in synchronized cells and remained high during cell-cycle progression. These data indicate that CNT1 adapts to cell-cycle progression and responds to nucleos(t)ide metabolism status, a feature that might contribute to the cytotoxic action of cell-cycle-dependent anticancer drugs.
Valdés
Raquel
R
Regulació dels Sistemes de Transport (RST), Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain.
Casado
F Javier
FJ
Pastor-Anglada
Marçal
M
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects; D016895:Culture Media, Serum-Free; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006918:Hydroxyurea / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000502:physiology; D008898:Mimosine / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism; D051381:Rats; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D016196:S Phase; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D009705:Nucleosides; C065171:cif nucleoside transporter; D008898:Mimosine; D004247:DNA; D012264:Ribonucleotide Reductases; D006918:Hydroxyurea