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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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