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Papers In Press, published online ahead of print December 8, 2003
J. Biol. Chem, 10.1074/jbc.M311659200
Submitted on October 23, 2003
Revised on November 20, 2003
Accepted on December 8, 2003

Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappa B

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

Dept. of Biochemistry and Molecular Biology, Unit 117, Univ. Texas M.D. Anderson Cancer Center, Houston, TX 77030

Corresponding Author: wsliao{at}mdanderson.org

Many cancers have constitutively activated NFkappa B whose elevation contributes to the cancer cells’ resistance to chemotherapeutic agent-induced apoptosis. Although mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) kinase kinase-3 (MEKK3) has been shown to participate in the activation of NFkappa B, 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 NFkappa B 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 NFkappa B activity. We show that stable cell lines overexpressing MEKK3 not only had elevated levels of NFkappa B-binding activity but also were more responsive to cytokine stimulation. These stable cells showed 2- to 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 PARP cleavage and dramatically increased resistance to apoptosis induced by TRAIL, doxorubicin, daunorubicin, camptothecin, and paclitaxel. Intriguingly, analysis of human breast and ovarian cancers showed a significant fraction of these samples have elevated MEKK3 protein levels with corresponding increases in NFkappa B 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 NF[kappa}B activity, increased expression of cell survival factors, and ultimately contribute 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.


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