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posted on 2023-04-03, 19:40 authored by Elena V. Knatko, Sally H. Ibbotson, Ying Zhang, Maureen Higgins, Jed W. Fahey, Paul Talalay, Robert S. Dawe, James Ferguson, Jeffrey T.-J. Huang, Rosemary Clarke, Suqing Zheng, Akira Saito, Sukirti Kalra, Andrea L. Benedict, Tadashi Honda, Charlotte M. Proby, Albena T. Dinkova-Kostova <p>Supplemental Figure S1. Spectral characteristics of UVA 340 lamps. Figure S2. Nrf2 disruption leads to an increase in the mRNA of Nrf3, but not Nrf1, in skin of SKH-1 hairless mice. Figure S3. TBE-31 treatment induces NQO1 in dermis and epidermis of WT SKH-1 hairless mice, but has no effect in Nrf2-KO animals. Figure S5. The architecture of the skin is similar among WT, Nrf2-KO and Keap1-KD SKH-1 hairless mice. Figure S6. Dose optimization for the use of TBE-31 as a pharmacological agent for protection against cutaneous carcinogenesis mediated by solar-simulated UV radiation. Figure S7. Optimization of azathioprine treatment in SKH-1 hairless mice. Figure S8. HPLC analysis of the sulforaphane (SF, active)- and glucoraphanin (GR, placebo) extracts used in the human study. Figure S9. NQO1 inducer activity of the sulforaphane (SF, active)- and glucoraphanin (GR, placebo) extracts used in the human study.</p>
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ARTICLE 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. Cancer Prev Res; 8(6); 475–86. ©2015 AACR.
