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.
Highlights
Epithelial skin cancers are the most frequent malignancies in humans
K5cre-caNrf2 mice were subjected to a DMBA/tetradecanoylphorbol 13-acetate (TPA)-induced skin carcinogenesis protocol [18]
NRF2 activation is a promising strategy for chemoprevention of cancer, and natural and synthetic NRF2-activating compounds are in clinical trials for cancer prevention in high-risk patients [9]
Summary
Epithelial skin cancers are the most frequent malignancies in humans. Reactive oxygen species (ROS) are important in this process, since they cause DNA damage and thereby promote malignant transformation [1]. To counteract the deleterious effects of ROS, cells have developed antioxidant defense strategies. Of particular importance is the transcription factor nuclear factor erythroid derived 2, like 2 (Nrf2), which regulates the expression of antioxidant proteins and enzymes involved in ROS or xenobiotic detoxification [2]. Because of these important functions, loss of Nrf has detrimental
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