Effects of RIα Overexpression on Cisplatin Sensitivity in Human Ovarian Carcinoma Cells

doi:10.1006/bbrc.1998.9223

Biochemical and Biophysical Research Communications

Volume 249, Issue 3, 28 August 1998, Pages 723-727

https://doi.org/10.1006/bbrc.1998.9223 Get rights and content

Abstract

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 RIα mutants. These data suggest that mutation of RIα may confer resistance to cisplatin by affecting DNA repair activity. In the present study, we overexpressed RIα in human ovarian carcinoma A2780 cells to demonstrate that RIα can modulate cellular sensitivity to cisplatin. Retroviral-infected A2780 cells overexpressing wild-type RIα cDNA displayed a four- to eightfold greater sensitivity to cisplatin compared with parental cells. Overexpression of RIα in the CP70 cisplatin-resistant derivative of A2780 also increased the sensitivity of these cells to cisplatin. Therefore, enhanced expression of the RIα subunit of PKA sensitizes cells to the cytotoxic effects of this DNA-damaging agent. These data suggest that RIα may act directly, independent of the C subunit, to influence cellular sensitivity to cisplatin. Therefore, modulation of RIα expression or its functional status by pharmacological agents may potentially reverse cisplatin resistance in tumors.

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^☆: Marinoa, N.

¹: To whom correspondence should be addressed at 195 Little Albany St., New Brunswick, NJ 08901. Fax: 732-235-7493. E-mail:[email protected].

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Regular ArticleEffects of RIα Overexpression on Cisplatin Sensitivity in Human Ovarian Carcinoma Cells☆

Abstract

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Pharmacol. Therap.

Mutat. Res.

J. Urol.

Jpn. J. Pharmacol.

FEBS Lett.

Science

Oncogene

Biochem. Biophys. Res. Commun.

Regular Article
Effects of RIα Overexpression on Cisplatin Sensitivity in Human Ovarian Carcinoma Cells☆