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Originally published In Press as doi:10.1074/jbc.M204654200 on June 24, 2002

J. Biol. Chem., Vol. 277, Issue 35, 31407-31415, August 30, 2002
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Overexpression of the Atypical Protein Kinase C zeta  Reduces Topoisomerase II Catalytic Activity, Cleavable Complexes Formation, and Drug-induced Cytotoxicity in Monocytic U937 Leukemia Cells*

Isabelle PloDagger §, Hélène HernandezDagger , Glenda Kohlhagen, Dominique LautierDagger , Yves Pommier, and Guy LaurentDagger ||**

From the Dagger  INSERM E9910, Institut Claudius Régaud, 20 rue du Pont Saint Pierre, 31052 Toulouse cedex, France, the  Laboratory of Molecular Pharmacology, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, and the || Service d'Hématologie, Centre Hospitalier Universitaire Purpan, 31059 Toulouse, France

In this study, we evaluated the influence of protein kinase Czeta (PKCzeta ) on topoisomerase II inhibitor-induced cytotoxicity in monocytic U937 cells. In U937-zeta J and U937-zeta B cells, enforced PKCzeta expression, conferred by stable transfection of PKCzeta cDNA, resulted in total inhibition of VP-16- and mitoxantrone-induced apoptosis and decreased drug-induced cytotoxicity, compared with U937-neo control cells. In PKCzeta -overexpressing cells, drug resistance correlated with decreased VP-16-induced DNA strand breaks and DNA protein cross-links measured by alkaline elution. Kinetoplast decatenation assay revealed that PKCzeta overexpression resulted in reduced global topoisomerase II activity. Moreover, in PKCzeta -overexpressing cells, we found that PKCzeta interacted with both alpha  and beta  isoforms of topoisomerase II, and these two enzymes were constitutively phosphorylated. However, when human recombinant PKCzeta (rH-PKCzeta ) was incubated with purified topoisomerase II isoforms, rH-PKCzeta interacted with topoisomerase IIbeta but not with topoisomerase IIalpha . PKCzeta /topoisomerase IIbeta interaction resulted in phosphorylation of this enzyme and in decrease of its catalytic activity. Finally, this report shows for the first time that topoisomerase IIbeta is a substrate for PKCzeta , and that PKCzeta may significantly influence topoisomerase II inhibitor-induced cytotoxicity by altering topoisomerase IIbeta activity through its kinase function.

* This work was supported in part by l'Association pour la Recherche sur le Cancer grant 5526 (to G. L.), La Faculté de Médecine Toulouse-Rangueil (to G. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ A recipient of a fellowship from la Ligue Nationale Contre le Cancer. To whom correspondence may be addressed: INSERM E9910, Institut Claudius Régaud, 20 rue du Pont Saint Pierre, 31052 Toulouse cedex, France. Tel.: 33-5-61-42-41-73; Fax: 33-5-61-42-46-06; E-mail: plo@icr.fnclcc.fr.

** To whom correspondence may be addressed: INSERM E9910, Institut Claudius Régaud, 20 rue du Pont Saint Pierre, 31052 Toulouse cedex, France. Tel.: 33-5-61-42-41-73; Fax: 33-5-61-42-46-06; E-mail: laurent@icr.fnclcc.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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