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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.
Cancer Res. 2007 Oct 15; 67(20):10004-11.CR

Abstract

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-kappaB (NF-kappaB) and IkappaBalpha kinase, IkappaBalpha 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-kappaB 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.

Authors+Show Affiliations

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17942934

Citation

Ahn, Kwang Seok, et al. "Deficiency of NRH:quinone Oxidoreductase 2 Differentially Regulates TNF Signaling in Keratinocytes: Up-regulation of Apoptosis Correlates With Down-regulation of Cell Survival Kinases." Cancer Research, vol. 67, no. 20, 2007, pp. 10004-11.
Ahn KS, Gong X, Sethi G, et al. Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases. Cancer Res. 2007;67(20):10004-11.
Ahn, K. S., Gong, X., Sethi, G., Chaturvedi, M. M., Jaiswal, A. K., & Aggarwal, B. B. (2007). Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases. Cancer Research, 67(20), 10004-11.
Ahn KS, et al. Deficiency of NRH:quinone Oxidoreductase 2 Differentially Regulates TNF Signaling in Keratinocytes: Up-regulation of Apoptosis Correlates With Down-regulation of Cell Survival Kinases. Cancer Res. 2007 Oct 15;67(20):10004-11. PubMed PMID: 17942934.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases. AU - Ahn,Kwang Seok, AU - Gong,Xing, AU - Sethi,Gautam, AU - Chaturvedi,Madan M, AU - Jaiswal,Anil K, AU - Aggarwal,Bharat B, PY - 2007/10/19/pubmed PY - 2007/12/13/medline PY - 2007/10/19/entrez SP - 10004 EP - 11 JF - Cancer research JO - Cancer Res VL - 67 IS - 20 N2 - 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-kappaB (NF-kappaB) and IkappaBalpha kinase, IkappaBalpha 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-kappaB 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/17942934/Deficiency_of_NRH:quinone_oxidoreductase_2_differentially_regulates_TNF_signaling_in_keratinocytes:_up_regulation_of_apoptosis_correlates_with_down_regulation_of_cell_survival_kinases_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17942934 DB - PRIME DP - Unbound Medicine ER -