Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)475-486
Number of pages12
JournalCancer Prevention Research
Volume8
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Radiation
Skin Neoplasms
Carcinogens
Carcinogenesis
Hairless Mouse
Neoplasms
Skin
Azathioprine
Erythema
Immunosuppressive Agents
Interleukin-6
Healthy Volunteers
Oxidative Stress
Transcription Factors
Up-Regulation
Biomarkers
Incidence
Proteins
Therapeutics
sulforafan

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Knatko, E. V., Ibbotson, S. H., Zhang, Y., Higgins, M., Fahey, J. W., Talalay, P., ... Dinkova-Kostova, A. T. (2015). Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans. Cancer Prevention Research, 8(6), 475-486. https://doi.org/10.1158/1940-6207.CAPR-14-0362

Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans. / 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.

In: Cancer Prevention Research, Vol. 8, No. 6, 01.06.2015, p. 475-486.

Research output: Contribution to journalArticle

Knatko, EV, Ibbotson, SH, Zhang, Y, Higgins, M, Fahey, JW, Talalay, P, Dawe, RS, Ferguson, J, Huang, JTJ, Clarke, R, Zheng, S, Saito, A, Kalra, S, Benedict, AL, Honda, T, Proby, CM & Dinkova-Kostova, AT 2015, 'Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans', Cancer Prevention Research, vol. 8, no. 6, pp. 475-486. https://doi.org/10.1158/1940-6207.CAPR-14-0362
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. / Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans. In: Cancer Prevention Research. 2015 ; Vol. 8, No. 6. pp. 475-486.
@article{6376d4e823e34a5b9b73a69767166b93,
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.",
author = "Knatko, {Elena V.} and Ibbotson, {Sally H.} and Ying Zhang and Maureen Higgins and Fahey, {Jed W} and Paul Talalay and Dawe, {Robert S.} and James Ferguson and Huang, {Jeffrey T J} and Rosemary Clarke and Suqing Zheng and Akira Saito and Sukirti Kalra and Benedict, {Andrea L.} and Tadashi Honda and Proby, {Charlotte M.} and Dinkova-Kostova, {Albena T.}",
year = "2015",
month = "6",
day = "1",
doi = "10.1158/1940-6207.CAPR-14-0362",
language = "English (US)",
volume = "8",
pages = "475--486",
journal = "Cancer Prevention Research",
issn = "1940-6207",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans

AU - Knatko, Elena V.

AU - Ibbotson, Sally H.

AU - Zhang, Ying

AU - Higgins, Maureen

AU - Fahey, Jed W

AU - Talalay, Paul

AU - Dawe, Robert S.

AU - Ferguson, James

AU - Huang, Jeffrey T J

AU - Clarke, Rosemary

AU - Zheng, Suqing

AU - Saito, Akira

AU - Kalra, Sukirti

AU - Benedict, Andrea L.

AU - Honda, Tadashi

AU - Proby, Charlotte M.

AU - Dinkova-Kostova, Albena T.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84940894533&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940894533&partnerID=8YFLogxK

U2 - 10.1158/1940-6207.CAPR-14-0362

DO - 10.1158/1940-6207.CAPR-14-0362

M3 - Article

C2 - 25804610

AN - SCOPUS:84940894533

VL - 8

SP - 475

EP - 486

JO - Cancer Prevention Research

JF - Cancer Prevention Research

SN - 1940-6207

IS - 6

ER -