Enhanced sensitivity of P-glycoprotein-positive multidrug resistant tumor cells to complement-mediated lysis.
The interaction of KB-V1, a multidrug resistant (MDR) variant of the KB-3-1 human oral carcinoma, with human complement was investigated. KB-V1 cells were found to be more sensitive than KB-3-1 cells to complement-mediated lysis. Detailed analysis of the capacity of KB cells to activate human complement demonstrated that both C3b deposition and formation of the membrane attack complex (MAC) are higher on KB-V1 than on KB-3-1 cells. Furthermore, the MAC formed on KB-V1 cells, but not on KB-3-1 cells, was found to be resistant to trypsin treatment, i.e. more stably inserted into the plasma membrane. Immunofluorescence analysis by flow cytometry showed that KB-V1 cells express less decay-accelerating factor (DAF, CD55) than KB-3-1 cells. Two other complement regulatory proteins, membrane cofactor protein (MCP, CD46) and CD59 are expressed to a similar extent on both KB-V1 and KB-3-1 cells. Treatment of KB-V1 cells with neutralizing anti-P-glycoprotein (P-gp) monoclonal antibodies reduced their sensitivity to complement. In addition, KB-V1 revertants which cease to express P-gp become more resistant to complement. These results indicate that multiple factors, such as reduced expression of DAF, enhanced deposition of C3b and increased binding and stability of the MAC may contribute to the increased complement sensitivity of KB-V1 cells. It is suggested that P-gp is responsible for the complement-sensitive phenotype of KB-V1 cells.
Bomstein
Y
Y
Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv University, Israel.
Fishelson
Z
Z
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology*; D018958:CD55 Antigens / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D003186:Complement C9 / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003165:Complement System Proteins / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D018432:Drug Resistance, Multiple; D006801:Humans; D011485:Protein Binding; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018958:CD55 Antigens; D003186:Complement C9; D015938:Complement Membrane Attack Complex; D003179:Complement C3b; D003165:Complement System Proteins