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J. Biol. Chem., Vol. 279, Issue 25, 26019-26027, June 18, 2004

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NF-B Activation by the Chemopreventive Dithiolethione Oltipraz Is Exerted through Stimulation of MEKK3 Signaling^*

Chu Won Nho and Peter J. O'Dwyer

From the Division of Hematology-Oncology, School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Chemoprevention by the dithiolethione analogue oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) may occur through several mechanisms, among them stimulation of detoxication activity. The phase II detoxication enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2) also known as quinone reductase (QR) is well established to undergo transcriptional activation following oltipraz treatment of colon cancer cells in culture. Promoter analysis of the QR gene in oltipraztreated cells reveals the involvement of both the AP-1 and NF-B elements in the response. The emerging role of NF-B in cell survival prompted a fuller analysis of effects of oltipraz on this pathway. Oltipraz treatment of both HCT116 and HT29 cells results in the induction of proteins involved in both pathways of NF-B activation, including p65, IB kinase (IKK), IB kinase (IKK), and NF-B-inducing kinase (NIK). IB total protein levels were unchanged, but phosphorylation of the inhibitor was also induced in both lines. Electrophoretic mobility shift assay (EMSA) analysis confirmed induction of protein binding to a consensus NF-B element, and transcriptional activation was further confirmed using a reporter construct. Transcriptional activation of QR was decreased in a dose-dependent manner by dominant-negative NF-B in both cell lines. The molecular mechanism that triggers IKK activation in response to oltipraz was also examined using inhibitory constructs of NIK and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). We found that both MEKK3 and NIK exert effects on IKK/ activation, but through different pathways. Furthermore, the receptor-interacting protein (RIP) was found to interact strongly with MEKK3 during oltipraz-induced NF-B signaling, implying a role for tumor necrosis factor receptor signaling in the action of oltipraz. These results implicate a novel signaling pathway for the action of oltipraz in QR gene regulation.

Received for publication, August 14, 2003 , and in revised form, March 24, 2004.

^* This work was supported by Grant CA-78272 from the NCI, National Institutes of Health. 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: School of Medicine, 51 N. 39th St., MAB-103, Philadelphia, PA 19104. Tel.: 215-662-8636; Fax: 215-243-3269; E-mail: peter.odwyer{at}uphs.upenn.edu.

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