Effects of RIalpha overexpression on cisplatin sensitivity in human ovarian carcinoma cells

Our laboratory has found that Chinese hamster ovary (CHO) and mouse Y1 adrenocortical carcinoma PKA mutants with a defective R subunit, but not altered C subunits, exhibit increased resistance to cisplatin as well as other DNA-damaging agents. The mechanism of resistance may be associated with incre...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 1998-08, Vol.249 (3), p.723-727
Main Authors: Cvijic, M E, Chin, K V
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
CHO Cells
Cisplatin - pharmacology
Cricetinae
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
Cyclic AMP-Dependent Protein Kinases - chemistry
Cyclic AMP-Dependent Protein Kinases - genetics
Cyclic AMP-Dependent Protein Kinases - metabolism
DNA Damage
DNA Repair
Drug Resistance - genetics
Drug Resistance - physiology
Female
Gene Expression
Humans
Mice
Mutation
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - enzymology
Ovarian Neoplasms - genetics
Protein Conformation
Tumor Cells, Cultured
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Summary:Our laboratory has found that Chinese hamster ovary (CHO) and mouse Y1 adrenocortical carcinoma PKA mutants with a defective R subunit, but not altered C subunits, exhibit increased resistance to cisplatin as well as other DNA-damaging agents. The mechanism of resistance may be associated with increased recognition of the cisplatin-damaged DNA and protein binding to the DNA lesion, thus enhancing DNA repair in the RI alpha mutants. These data suggest that mutation of RI alpha may confer resistance to cisplatin by affecting DNA repair activity. In the present study, we overexpressed RI alpha in human ovarian carcinoma A2780 cells to demonstrate that RI alpha can modulate cellular sensitivity to cisplatin. Retroviral-infected A2780 cells overexpressing wild-type RI alpha cDNA displayed a four- to eightfold greater sensitivity to cisplatin compared with parental cells. Overexpression of RI alpha in the CP70 cisplatin-resistant derivative of A2780 also increased the sensitivity of these cells to cisplatin. Therefore, enhanced expression of the RI alpha subunit of PKA sensitizes cells to the cytotoxic effects of this DNA-damaging agent. These data suggest that RI alpha may act directly, independent of the C subunit, to influence cellular sensitivity to cisplatin. Therefore, modulation of RI alpha expression or its functional status by pharmacological agents may potentially reverse cisplatin resistance in tumors.
ISSN:0006-291X