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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA
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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA

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Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations

Frank Rolfs1, Marcel Huber2, Andreas Kuehne3

  • 1Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

Cancer Research
|November 5, 2015
PubMed

Insights

Activating the NRF2 pathway, often linked to cancer prevention, unexpectedly promotes skin tumor development. This study reveals NRF2’s protumorigenic role in early cancer stages, challenging its preventive potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The transcription factor NRF2 is investigated for its potential in cancer prevention.
  • Previous research suggested NRF2 activation as a cancer prevention strategy.
  • This study explores potential limitations of NRF2 activation in cancer prevention.

Purpose of the Study:

  • To investigate the role of Nrf2 in murine tumorigenesis, specifically in keratinocytes.
  • To identify the metabolic alterations induced by Nrf2 in keratinocytes.
  • To assess the clinical relevance of NRF2 activation in human skin precancerous lesions.

Main Methods:

  • Murine tumorigenesis experiments were conducted to evaluate Nrf2 effects.
  • Metabolic pathways, including glutathione biosynthesis and the oxidative pentose phosphate pathway, were analyzed.
  • Analysis of NRF2 and target gene activation in human actinic keratoses.

Main Results:

  • Nrf2 expression conferred protumorigenic metabolic alterations in murine keratinocytes.
  • Increased NADPH, purine, and glutathione levels promoted survival of oncogenic keratinocytes.
  • Nrf2's protumorigenic activity was significant in a non-chemical carcinogenesis skin tumor model.
  • Activated NRF2 and target genes were observed in human actinic keratoses.

Conclusions:

  • Activated NRF2 exhibits unexpected tumor-promoting activity during early skin tumorigenesis.
  • NRF2's role in keratinocyte metabolism can support the survival of pre-cancerous cells.
  • Findings challenge the paradigm of NRF2 as solely a cancer preventive factor and highlight its complex role.

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