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J. Biol. Chem., Vol. 278, Issue 28, 25461-25467, July 11, 2003

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c-Jun N-terminal Kinase Contributes to Apoptotic Synergy Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand plus DNA Damage in Chemoresistant, p53 Inactive Mesothelioma Cells^*

Claire Vivo, Weihong Liu and V. Courtney Broaddus 

From the Lung Biology Center, San Francisco General Hospital, University of California, San Francisco, California 94143-0854

Apoptotic resistance of cancer cells may be overcome by the combination of treatments that activate the two major apoptotic pathways: (i) the death receptor pathway activated by death ligands and (ii) the DNA damage pathway activated by chemotherapy. We have previously shown that mesothelioma cells, resistant to most treatments, are sensitive to the combination of the death ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL/Apo2L) plus chemotherapy. We investigated a possible role for c-Jun N-terminal kinase (JNK) in the synergistic effect, knowing that JNK can be activated separately by TRAIL and by DNA damage. We chose to study the M28 and REN human mesothelioma cell lines, which are p53-inactivated, to avoid an interaction between p53 and JNK. We showed that JNK was activated by TRAIL and by etoposide and that the activation was enhanced by the combination of the two treatments. We found this activation to be caspase-independent. To inhibit the JNK pathway, we used either dominant-negative constructs of JNK1 and JNK2 (compared with dominant-negative caspase 9) or a chemical inhibitor of the JNK pathway (SP600125). In cells treated with TRAIL plus etoposide, JNK inhibition increased cell survival and decreased apoptosis significantly. In transfected M28 cells, the effect of JNK inhibition was as great as that of the dominant-negative caspase 9 construct. We conclude that JNK contributes to the synergistic effect of TRAIL combined with DNA damage by mediating signals independent of p53 leading to apoptosis.

Received for publication, March 3, 2003 , and in revised form, April 15, 2003.

^* This work was supported by National Institutes of Health Grants RO1 ES08985 and RO1 CA95671 and by a grant from the American Lung Association of California Research Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Lung Biology Center, Box 0854, University of California San Francisco, San Francisco, CA 94143-0854. E-mail: sfcourt{at}itsa.ucsf.edu.

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