Over-expression of multidrug resistance P-glycoprotein inhibits NK granule-mediated lytic ability without affecting the Fas lytic pathway.
Multidrug resistance (MDR) in tumor cells is commonly associated wich the over-expression of P-glycoprotein (Pgp), the product of the MDR1 gene. In this study, we investigated whether over-expression of Pgp in natural killer (NK) cells would influence their granule- as well as fas-mediated cytolytic activities. YT-INDY, a human NK-like cell line, was transfected with the MDR 1 gene, then tested for Pgp activity the presence of various concentrations of R-verapamil, a potent Pgp inhibitor. We showed that, unlike control YT-INDY, the Pgp activity of the transfectants (YT-mdr(+)) was only partially inhibited by R-verapamil. We also showed that Fas lytic activity was unaltered and that the loss of granule-mediated cytotoxicity was not due to reduced LFA-1 expression or to a decrease in target cell (TC) binding. Our data indicate that Pgp may be involved in the release of cytotoxic molecules.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D018118:Chloride Channels / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D018432:Drug Resistance, Multiple / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis; D014700:Verapamil / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism*