Differential expression of regulatory proteins in L1210/VCR cells with multidrug resistance mediated by P-glycoprotein.

Phosphorylation of P-glycoprotein (PGP) by some protein kinases may play an important role in the regulation of its drug transport activity, and may also be important for the development of multidrug resistance (MDR) phenotype. In the present study we investigated the expression of three groups of mitogen-activated protein kinases (MAPKs). The expression of ERKs, SAPK/JNKs and p38-MAPK was studied at the protein level in sensitive (L1210) and multidrug resistant (L1210/VCR) cells. The expression of ERKs in multidrug resistant cells did not differ from those observed in parental sensitive cells. On the other hand, the development of multidrug resistance phenotype in L1210/VCR cells was associated with increased expression of cytosolic p38-MAPK and also proteins of 90 and 130 kDa that react with antibody specific for SAPK/JNKs. The expression of the proteins mentioned was stimulated above all in conditions when vincristine was present in cultivation medium and the stimulation of transport activity of PGP was necessary for the cell survival. The development of multidrug resistance phenotype in L1210/VCR cells was not associated with significant changes in expression of several heat-shock proteins (hsp25, hsp60, hsp70, hsp90). The levels of these proteins were comparable in sensitive L1210 and resistant L1210/VCR cells, and vincristine did not influence the expression of heat-shock proteins in resistant cells.