title: Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations.
abstract: Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis.
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Rolfs
authors.affiliation: Service de Dermatologie et Vénéréologie, Hôpital de Beaumont, Université de Lausanne, Lausanne, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Huber
authors.affiliation: Department of Biology, Institute for Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuehne
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kramer
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Haertel
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Sukalp
authors.initials: S
authors.lastname: Muzumdar
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Tanner
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Friederike
authors.initials: F
authors.lastname: Böhm
authors.affiliation: Institute of Virology, Saarland University, Homburg, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
authors.affiliation: Department of Biology, Institute for Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
authors.affiliation: Service de Dermatologie et Vénéréologie, Hôpital de Beaumont, Université de Lausanne, Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. matthias.schaefer@biol.ethz.ch sabine.werner@biol.ethz.ch.
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. matthias.schaefer@biol.ethz.ch sabine.werner@biol.ethz.ch.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002470:Cell Survival; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D055623:Keratosis, Actinic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse