Inactivation of the quinone oxidoreductases NQO1 and NQO2 strongly elevates the incidence and multiplicity of chemically induced skin tumors.
The cytosolic quinone oxidoreductases NQO1 and NQO2 protect cells against oxidative stress by detoxifying quinones and preventing redox cycling. In this study, we used double knockout (DKO) mice deficient for NQO1 and NQO2 to investigate the role of these antioxidative enzymes in a two-stage model of inflammatory skin carcinogenesis. In this model, tumors are caused by exposure to topical carcinogen dimethylbenz(a)anthracene or benzo(a)pyrene (BP) followed by twice weekly application of proinflammatory phorbol 12-myristate 13-acetate. On this classic chemical carcinogenesis protocol, DKO mice showed a significantly higher skin tumor frequency and multiplicity compared with control wild-type or single knockout mice. Analysis of skin from wild-type and DKO mice exposed to BP for 6, 12, or 24 hours revealed a relative delay in the activation of p53, p63, p19ARF, and apoptosis in DKO mice, consistent with a negative modifier role for NQO1/NQO2 in carcinogenesis. Our findings offer genetic evidence of the significance of quinone oxidoreductases NQO1 and NQO2 in limiting chemical skin carcinogenesis.
Shen
Jun
J
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Barrios
Roberto J
RJ
Jaiswal
Anil K
AK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001551:Benz(a)Anthracenes; D001564:Benzo(a)pyrene; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency / Q000235:genetics*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011808:Quinone Reductases / Q000172:deficiency / Q000235:genetics*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D001551:Benz(a)Anthracenes; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C046810:7,12-dihydroxymethylbenz(a)anthracene; D001564:Benzo(a)pyrene; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D053148:Caspase 3; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate