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J. Biol. Chem., Vol. 281, Issue 29, 19798-19808, July 21, 2006

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Genetic Deletion of NAD(P)H:Quinone Oxidoreductase 1 Abrogates Activation of Nuclear Factor-B, IB Kinase, c-Jun N-terminal Kinase, Akt, p38, and p44/42 Mitogen-activated Protein Kinases and Potentiates Apoptosis^*

Kwang Seok Ahn, Gautam Sethi, Abhinav K. Jain, Anil K. Jaiswal, and Bharat B. Aggarwal¹

From the Cytokine Research Laboratory, Department of Experimental Therapeutics, M. D. Anderson Cancer Center, The University of Texas and the Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030

The NAD(P)H:quinone oxidoreductase 1 (NQO1) is a phase II enzyme that reduces and detoxifies quinones and their derivatives. Although overexpressed in tumor cells, the NQO1 has been linked with the suppression of carcinogenesis, and the effect of NQO1 on tumor necrosis factor (TNF), a cytokine that mediates tumorigenesis through proliferation, invasion, angiogenesis, and metastasis of tumors, is currently unknown. The purpose of our study was to determine the role of NQO1 in TNF cell signaling by using keratinocytes derived from wild-type and NQO1 gene-deleted mice. TNF induced nuclear factor (NF)-B activation in wild-type but not in NQO1-deleted cells. The treatment of wild-type cells with dicoumarol, a known inhibitor of NQO1, also abolished TNF-induced NF-B activation. NF-B activation induced by lipopolysaccharide, phorbol ester, and cigarette smoke, was also abolished in NQO1-deleted cells. The suppression of NF-B activation was mediated through the inhibition of IB kinase activation, IB phosphorylation, and IB degradation. Further, the deletion of NQO1 abolished TNF-induced c-Jun N-terminal kinase, Akt, p38, and p44/p42 mitogen-activated protein kinase activation. TNF also induced the expression of various NF-B-regulated gene products involved in cell proliferation, antiapoptosis, and invasion in wild-type NQO1 keratinocytes but not in NQO1-deleted cells. The suppression of these antiapoptotic gene products increased TNF-induced apoptosis in NQO1-deleted cells. We also found that TNF activated NQO1, and NQO1-specific small interfering RNA abolished the TNF-induced NQO1 activity and NF-B activation. Overall, our results indicate that NQO1 plays a pivotal role in signaling activated by TNF and other inflammatory stimuli and that its suppression is a potential therapeutic strategy to inhibit the proliferation, survival, invasion, and metastasis of tumor cells.

Received for publication, February 7, 2006 , and in revised form, May 8, 2006.

^* This work was supported by the Clayton Foundation for Research (to B. B. A.), Department of Defense U.S. Army Breast Cancer Research Program Grant BC010610 (to B. B. A.), National Institutes of Health (NIH) Grant PO1 CA91844 for lung chemoprevention (to B. B. A.), and an NIH P50 Head and Neck SPORE grant (to B. B. A.). 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.

¹ The Ransom Horne Jr. Professor of Cancer Research. To whom correspondence should be addressed: Cytokine Research Laboratory, Dept. of Experimental Therapeutics, M. D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, TX 77030. Tel.: 713-794-1817; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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