Correlation of protein kinase C translocation, P-glycoprotein phosphorylation and reduced drug accumulation in multidrug resistant human KB cells.
Treatment of drug-resistant human KB carcinoma cells (KB-V1) with 0.2 microM phorbol 12-myristate 13-acetate (PMA) resulted in increases of 4-fold in both membrane-associated protein kinase C activity and phosphorylation of P-glycoprotein. The response was essentially complete after 30 min and was relatively stable, since both of these parameters remained elevated above basal levels in cells exposed to PMA for 24 hours. In contrast, long-term PMA treatment of drug-sensitive KB-3 cells caused complete depletion of protein kinase C. The rate of accumulation of [3H]vinblastine in KB-V1 cells was 0.8 +/- 0.1 pmol/mg/30 min in the absence, and 1.9 +/- 0.2 pmol/mg/30 min in the presence, of 20 microM verapamil. Preincubation of cells with PMA resulted in a time-dependent decrease, up to 60% after 24 hours, in both of these values. These results suggest that protein kinase C mediated phosphorylation stimulates the drug transport activity of P-glycoprotein.
Chambers
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Department of Biological Chemistry, Merck Sharp & Dohme Research Laboratory, West Point, PA 19486.
Chalikonda
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Eilon
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004351:Drug Resistance; D006801:Humans; D007624:KB Cells / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D014747:Vinblastine; D014700:Verapamil; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate