Expression of the antisense cDNA for protein kinase C alpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells.
Multidrug resistance is functionally associated with the expression of a plasma membrane energy-dependent drug efflux pump termed P-glycoprotein, the product of the mdr1 gene. Transfection of P-glycoprotein-expressing doxorubicin-resistant MCF-7 cells with an expression vector containing the cDNA for protein kinase C alpha in the antisense orientation reduces protein kinase C alpha levels and decreases total protein kinase C activity by 75%. This is accompanied by reduced phosphorylation of P-glycoprotein, a 2-fold increase in drug retention, and a 3-fold increase in doxorubicin cytotoxicity. These results provide further evidence that protein kinase C alpha can positively regulate multidrug resistance in MCF-7 cells through posttranslational phosphorylation of P-glycoprotein.
Ahmad
S
S
Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. 20007.
Glazer
R I
RI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D016373:DNA, Antisense / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D016373:DNA, Antisense; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D011493:Protein Kinase C