Transfection with protein kinase C alpha confers increased multidrug resistance to MCF-7 cells expressing P-glycoprotein.
Cross-resistance to anticancer drugs, termed multidrug resistance (mdr), has been functionally associated with the expression of a plasma membrane energy-dependent efflux pump, termed P-glycoprotein, the product of the mdr1 gene. When MCF-7 breast carcinoma cells were transfected with the human mdr1 gene (BC-19 cells), they expressed levels of P-glycoprotein equivalent to those of cells selected for resistance to doxorubicin (MCF-7/ADR) but exhibited 10- to 50-fold less resistance to doxorubicin and vinblastine. We have now demonstrated that when BC-19 cells were stably transfected with protein kinase C alpha (PKC alpha), resistance to doxorubicin and vinblastine was increased; wild-type MCF-7 cells transfected with PKC alpha did not exhibit any change in drug resistance. Increased resistance in PKC alpha-transfected BC-19 cells was associated with enhanced PKC activity and phosphorylation of P-glycoprotein and decreased drug accumulation. The PKC activator, phorbol dibutyrate, further increased resistance to doxorubicin and stimulated P-glycoprotein phosphorylation. These results demonstrate that transfection of P-glycoprotein-expressing cells with PKC resulted in increased mdr and that PKC may have served as an important modulator of this process.
Yu
G
G
Laboratory of Biological Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Ahmad
S
S
Aquino
A
A
Fairchild
C R
CR
Trepel
J B
JB
Ohno
S
S
Suzuki
K
K
Tsuruo
T
T
Cowan
K H
KH
Glazer
R I
RI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002460:Cell Line; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D014162:Transfection; D014410:Tumor Stem Cell Assay
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D011493:Protein Kinase C