Inhibition of Nucleoside Transport by p38 MAPK Inhibitors

• Published in: The Journal of biological chemistry 2002-08, Vol.277 (32), p.28364-28367
• Main Authors: Huang, Min, Wang, Yanhong, Collins, Matthew, Gu, Jing Jin, Mitchell, Beverly S, Graves, Lee M
• Format: Article
• Language: English
• Subjects: AraC Transcription Factor; Bacterial Proteins; Biological Transport; Cell Membrane - metabolism; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Erythrocytes - cytology; Humans; K562 Cells; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Models, Chemical; Nucleosides - metabolism; p38 Mitogen-Activated Protein Kinases; Protein Binding; Repressor Proteins - pharmacokinetics; Transcription Factors; Uridine - pharmacokinetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C200321200

While investigating the ability of p38 MAPK to regulate cytarabine (Ara C)-dependent differentiation of erythroleukemia K562 cells, we observed effects that indicated that the imidazoline class of p38 MAPK inhibitors prevented nucleoside transport. Incubation of K562 cells with SB203580, SB203580-iodo, or SB202474, an analogue of SB203580 that does not inhibit p38 MAPK activity, inhibited the uptake of [ 3 H]Ara C or [ 3 H]uridine and the differentiation of K562 cells. Consistent with the effects of these compounds on the nitrobenzylthioinosine (NBMPR)-sensitive equilibrative nucleoside transporter (ENT1), incubation with SB203580 or SB203580-iodo eliminated the binding of [ 3 H]NBMPR to K562 cells or membranes isolated from human erythrocytes. Furthermore, using a uridine-dependent cell type (G9c), we observed that SB203580 or SB203580-iodo efficiently inhibited the salvage synthesis of pyrimidine nucleotides in vivo . Thus these studies demonstrate that the NBMPR-sensitive equilibrative nucleoside transporters are novel and unexpected targets for the p38 MAPK inhibitors at concentrations typically used to inhibit protein kinases.