Transfer of adriamycin resistance by fusion of Mr 170,000 P-glycoprotein to the plasma membrane of sensitive cells.
One of the characteristics of multidrug-resistant mammalian cells is the presence of a glycoprotein of approximately Mr 170,000 in their cell membrane. Termed P-glycoprotein, this glycoprotein is thought to be the gene product of an amplified gene cloned and sequenced from a cell line (LZ) which is highly resistant to Adriamycin and cross-resistant to actinomycin D, colchicine, and vincristine. Resistance to Adriamycin has been induced in sensitive cells by chromosome or gene transfer. We now show that P-glycoprotein isolated from LZ cells and fused to sensitive V79 Chinese hamster cells renders the latter transiently resistant to Adriamycin. Incorporation of P-glycoprotein was confirmed by immunoperoxidase staining of fusion products following treatment with antibody to P-glycoprotein and by Western blots of membrane preparations from fusion products. These results suggest that P-glycoprotein is one of the important factors in the expression of Adriamycin resistance and provide added confirmation that it may be the important product of gene amplification in multidrug-resistant cells. The results also suggest that the cell membrane may be one of several targets for Adriamycin cytotoxicity and that P-glycoprotein may be a binding site for Adriamycin, rendering the latter ineffective in registering sufficient membrane damage for cell killing.
Belli
J A
JA
Department of Radiation Therapy, University of Texas Medical Branch, Galveston 77550-2777.
Zhang
Y
Y
Fritz
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance; D007124:Immunoenzyme Techniques; D008562:Membrane Glycoproteins / Q000502:physiology*; D008970:Molecular Weight; D010641:Phenotype
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D004317:Doxorubicin