Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans

• Published in: Cancer prevention research (Philadelphia, Pa.) Pa.), 2015-06, Vol.8 (6), p.475-486
• Main Authors: Knatko, Elena V, Ibbotson, Sally H, Zhang, Ying, Higgins, Maureen, Fahey, Jed W, Talalay, Paul, Dawe, Robert S, Ferguson, James, Huang, Jeffrey T-J, Clarke, Rosemary, Zheng, Suqing, Saito, Akira, Kalra, Sukirti, Benedict, Andrea L, Honda, Tadashi, Proby, Charlotte M, Dinkova-Kostova, Albena T
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - metabolism; Blotting, Western; Female; Healthy Volunteers; Humans; Mice; Mice, Hairless; Mice, Inbred C57BL; Mice, Knockout; Neoplasms, Radiation-Induced - etiology; Neoplasms, Radiation-Induced - pathology; Neoplasms, Radiation-Induced - prevention & control; NF-E2-Related Factor 2 - physiology; Oxidative Stress - radiation effects; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Skin - metabolism; Skin - radiation effects; Skin Neoplasms - etiology; Skin Neoplasms - pathology; Skin Neoplasms - prevention & control; Solar Energy; Ultraviolet Rays - adverse effects
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.capr-14-0362

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.