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Molecular and Cellular Biology, October 2001, p. 6913-6926, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6913-6926.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Enhanced ROS Production in Oncogenically Transformed Cells Potentiates c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Activation and Sensitization to Genotoxic Stress

Moran Benhar, Idan Dalyot, David Engelberg,* and Alexander Levitzki*

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

Received 7 December 2000/Returned for modification 30 January 2001/Accepted 2 July 2001

Many primary tumors as well as transformed cell lines display high sensitivity to chemotherapeutic drugs and radiation. The molecular mechanisms that underlie this sensitivity are largely unknown. Here we show that the sensitization of transformed cells to stress stimuli is due to the potentiation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase pathways. Activation of these pathways by the antitumor drug cis-platin (CDDP) and by other stress agents is markedly enhanced and is induced by lower stress doses in NIH 3T3 cells overexpressing epidermal growth factor receptor, HER1-2 kinase, or oncogenic Ras than in nontransformed NIH 3T3 cells. Inhibition of stress kinase activity by specific inhibitors reduces CDDP-mediated cell death in transformed cells, whereas overactivation of stress kinase pathways augments cells death. Potentiation of stress kinases is a common feature of cells transformed by different oncogenes, including cells derived from human tumors, and is shown here to be independent of the activity of the particular transforming oncoprotein. We further show that the mechanism that underlies potentiation of stress kinases in transformed cells involves reactive oxygen species (ROS), whose production is elevated in these cells. JNK/p38 activation is inhibited by antioxidants and in particular by inhibitors of the mitochondrial respiratory chain and NADPH oxidase. Conversely, by artificially elevating ROS levels in nontransformed NIH 3T3 cells we were able to induce potentiation of JNK/p38 activation. Taken together, our findings suggest that ROS-dependent potentiation of stress kinase pathways accounts for the sensitization of transformed cells to stress and anticancer drugs.

* Corresponding author. Mailing address: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Phone for Alexander Levitzki: 972-2-6585404. Phone for David Engelberg: 972-2-6584718. Fax: 972-2-6512958. E-mail for Alexander Levitzki: Levitzki{at}VMS.HUJI.AC.IL. E-mail for David Engelberg: Engelber{at}VMS.HUJI.AC.IL.

Molecular and Cellular Biology, October 2001, p. 6913-6926, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6913-6926.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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