Regulation of P-glycoprotein expression in cyclic AMP-dependent protein kinase mutants.
Multidrug resistance (MDR) in cancer poses a major obstacle to the success of chemotherapy. We previously reported that cyclic AMP (cAMP)-resistant mutants of the Chinese hamster ovary and the mouse adrenal cortical carcinoma cells harboring defective regulatory (RI alpha) subunits of the cAMP-dependent protein kinase (PKA) are more sensitive than wild-type cells to chemotherapeutic agents that are substrates for P-glycoprotein. In addition, a transfectant overexpressing a mutant RI alpha cDNA showed similar increased sensitivity to these drugs. The altered drug sensitivity in the RI alpha mutants results from reduced expression of the mdr gene, suggesting that PKA may regulate its expression. In this study, we evaluated the sensitivity of several Chinese hamster ovary catalytic (C) subunit mutants to various anticancer drugs. Like the RI alpha subunit mutant, the C subunit mutants also exhibit decreased kinase activity and unresponsiveness to growth inhibition by cAMP. However, in contrast to the RI alpha subunit mutant, the C subunit mutants are not multidrug sensitive and maintain P-glycoprotein expression levels comparable to those of wild-type cells. Furthermore, the C subunit mutants display the same resistance patterns as wild-type cells to P-glycoprotein substrates, including Adriamycin, Taxol, and colchicine. No significant difference was observed in their sensitivity to non-MDR drugs, such as 5-fluorodeoxyuridine, between wild-type, RI alpha, and C subunit mutant cells. These results suggest that the increased multidrug sensitivity in the PKA mutant cells results from alteration of the RI alpha subunit and not the kinase activity, thus implying novel functions for the RI alpha subunit. Therefore, genetic alteration of the RI alpha subunit of PKA may modulate drug resistance in cancer.
Cvijic
M E
ME
Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick 08901, USA.
Chin
K V
KV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007624:KB Cells; D009154:Mutation; D011494:Protein Kinases / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C015482:protein kinase modulator; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases