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Deficiency of NRH:Quinone Oxidoreductase 2 Differentially Regulates TNF Signaling in Keratinocytes: Up-regulation of Apoptosis Correlates with Down-regulation of Cell Survival Kinases

¹ Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ² Department of Pharmacology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, Box 143, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3503 or 713-792-6459; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinones and quinoid compounds to hydroquinones. Although the role of a homologue, NAD(P)H:quinone oxidoreductase 1 (NQO1), is well defined in oxidative stress, neoplasia, and carcinogenesis, little is known about the mechanism of actions of NQO2 in these cellular responses. Whether NQO2 has any role in tumor necrosis factor (TNF) signaling was investigated using keratinocytes derived from wild-type and NQO2 knockout (NQO2^–/–) mice. Although exposure of wild-type cells to TNF led to activation of nuclear factor-B (NF-B) and IB kinase, IB degradation, p65 phosphorylation, and p65 nuclear translocation, this cytokine had no effect on NQO2^–/– cells. Deletion of NQO2 also abolished TNF-induced c-Jun NH₂-terminal kinase, Akt, p38, and p44/p42 mitogen-activated protein kinase activation. The induction of various antiapoptotic gene products (MMP-9, cyclin D1, COX-2, IAP1, IAP2, Bcl-2, cFLIP, and XIAP) by TNF was also abolished in NQO2^–/– cells. This correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, Annexin V staining, and caspase activation. In agreement with this, we also found that TNF activated NQO2, and NQO2-specific small interfering RNA abrogated the TNF-induced NQO2 activity and NF-B activation. Overall, our results indicate that deletion of NQO2 plays a differential role in TNF signaling pathway: by suppressing cell survival signals and potentiating TNF-induced apoptosis. [Cancer Res 2007;67(20):10004–11]

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