American Association for Cancer Research
00085472can150614-sup-146219_2_supp_0_npvm02.pdf (103.71 kB)

Supplemenatary Methods and References from Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations

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journal contribution
posted on 2023-03-31, 00:02 authored by Frank Rolfs, Marcel Huber, Andreas Kuehne, Stefan Kramer, Eric Haertel, Sukalp Muzumdar, Johanna Wagner, Yasmine Tanner, Friederike Böhm, Sigrun Smola, Nicola Zamboni, Mitchell P. Levesque, Reinhard Dummer, Hans-Dietmar Beer, Daniel Hohl, Sabine Werner, Matthias Schäfer

Description of additional methods and procedures used in the study. Also includes Supplementary References.



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. Cancer Res; 75(22); 4817–29. ©2015 AACR.