Correlation of altered tyrosine phosphorylation with methotrexate resistance in a cisplatin-resistant subline of L1210 cells.
Collateral resistance to cisplatin and methotrexate has been reported in several cell lines. A murine leukemia cell line (L1210/DDP) selected for cisplatin resistance also has been shown to be highly resistant to methotrexate. Of the mechanisms proposed for methotrexate resistance, only changes in methotrexate transport into the cells were found in an earlier report. Methotrexate enters mammalian cells via an active transport system. In the present study, we demonstrated that the transport into the cell may be impaired in the resistant cells due to altered tyrosine phosphorylation of a membrane protein with a molecular mass of 66 kDa. This alteration was manifested by altered tyrosine phosphorylation of the 66 kDa protein and may be an underlying modification that renders the cells resistant to methotrexate. These results suggest involvement of tyrosine phosphorylation in folate transport and methotrexate resistant in L1210/DDP cells.
Bhushan
A
A
Department of Pharmacology, University of Vermont College of Medicine, Burlington 05405, USA.
Wroblewski
D
D
Xuan
Y
Y
Tritton
T R
TR
Hacker
M P
MP
D000345:Affinity Labels; D000818:Animals; D001693:Biological Transport, Active; D015153:Blotting, Western; D002945:Cisplatin / Q000633:toxicity*; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D007939:Leukemia L1210 / Q000378:metabolism*; D008565:Membrane Proteins / Q000302:isolation & purification / Q000378:metabolism*; D008727:Methotrexate / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008970:Molecular Weight; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000345:Affinity Labels; D008565:Membrane Proteins; D010750:Phosphoproteins; D019000:Phosphotyrosine; D002945:Cisplatin; D008727:Methotrexate