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J. Biol. Chem., Vol. 279, Issue 9, 7576-7583, February 27, 2004

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Overexpression of MEKK3 Confers Resistance to Apoptosis through Activation of NFB^*

Ajoy K. Samanta, Helen J. Huang, Robert C. Bast, Jr., and Warren S.-L. Liao¶

From the Department of Biochemistry and Molecular Biology, Program in Genes and Development and the Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Many cancers have constitutively activated NFB, the elevation of which contributes to cancer cell resistance to chemotherapeutic agent-induced apoptosis. Although mitogen-activated protein kinase/extracellular-regulated kinase kinase kinase-3 (MEKK3) has been shown to participate in the activation of NFB, its relations to apoptosis and cancer are unclear. In this study, we established cell model systems to examine whether stable expression of MEKK3 could lead to increased NFB activity and confer resistance to apoptosis. In addition, we investigated in breast and ovarian cancers whether MEKK3 expression may be altered and correlated with aberrant NFB activity. We show that stable cell lines overexpressing MEKK3 not only had elevated levels of NFB binding activity but also were more responsive to cytokine stimulation. These stable cells showed 2–4-fold higher basal expression of Bcl-2 and xIAP than the parental cells. Consistent with this increased expression of cell survival genes, MEKK3 stable cells showed reduced activation of caspases 3 and 8 and poly(ADP-ribose) polymerase cleavage and dramatically increased resistance to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand, doxorubicin, daunorubicin, camptothecin, and paclitaxel. Intriguingly, analysis of human breast and ovarian cancers showed that a significant fraction of these samples have elevated MEKK3 protein levels with corresponding increases in NFB binding activities. Thus, our results established that elevated expression of MEKK3 appears to be a frequent occurrence in breast and ovarian cancers and that overexpression of MEKK3 in cells leads to increased NFB activity and increased expression of cell survival factors and ultimately contributes to their resistance to apoptosis. As such, MEKK3 may serve as a therapeutic target to control cancer cell resistance to cytokine- or drug-induced apoptosis.

Received for publication, October 23, 2003 , and in revised form, November 20, 2003.

^* This work was supported in part with funds from Pharmacia (to W. S.-L. L.) and by a Institutional Research Grant (to A. K. S.). 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: Dept. of Biochemistry and Molecular Biology, Unit 117, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: wsliao{at}mdanderson.org.

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