PMID: 9419412Jan 7, 1998Paper

Regulation of P-glycoprotein expression in cyclic AMP-dependent protein kinase mutants

Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research
M E Cvijic, K V Chin

Abstract

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 a...Continue Reading

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