title: Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans.
abstract: The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative, and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity, and burden of solar-simulated UV radiation-mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated are lower than those that arise in their wild-type counterparts. Pharmacologic Nrf2 activation by topical biweekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacologic Nrf2 activation lowers the expression of the pro-inflammatory factors IL6 and IL1β, and COX2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane reduced the degree of solar-simulated UV radiation-induced skin erythema, a quantifiable surrogate endpoint for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation.
authors: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Elena V
authors: EV
authors: Knatko
authors: Photobiology Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Sally H
authors: SH
authors: Ibbotson
authors: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Ying
authors: Y
authors: Zhang
authors: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Maureen
authors: M
authors: Higgins
authors: Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Center for Human Nutrition, Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
authors: Jed W
authors: JW
authors: Fahey
authors: Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Paul
authors: P
authors: Talalay
authors: Photobiology Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Robert S
authors: RS
authors: Dawe
authors: Photobiology Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: James
authors: J
authors: Ferguson
authors: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Jeffrey T-J
authors: JT
authors: Huang
authors: Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Rosemary
authors: R
authors: Clarke
authors: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York.
authors: Suqing
authors: S
authors: Zheng
authors: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York.
authors: Akira
authors: A
authors: Saito
authors: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Sukirti
authors: S
authors: Kalra
authors: Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Andrea L
authors: AL
authors: Benedict
authors: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York. Department of Chemistry, Stony Brook University, Stony Brook, New York.
authors: Tadashi
authors: T
authors: Honda
authors: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom. Photobiology Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Charlotte M
authors: CM
authors: Proby
authors: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom. Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. a.dinkovakostova@dundee.ac.uk.
authors: Albena T
authors: AT
authors: Dinkova-Kostova
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012993:Solar Energy; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger