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The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis

Oncogene volume 27, pages 4353–4362 (2008)Cite this article

Abstract

The impact of oxidative stress in human cancer has been extensively studied. It is accepted that elevated reactive oxygen species (ROS) promote mutagenic DNA damage. Even with an extensive armament of cellular antioxidants and detoxification enzymes, alterations to DNA occur that initiate cellular transformation. Erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) is a basic-region leucine zipper transcription factor that mediates the expression of key protective enzymes through the antioxidant-response element (ARE). By analysing 10 human prostate cancer microarray data sets, we have determined that Nrf2 and members of the glutathione-S-transferase (GST) mu family are extensively decreased in human prostate cancer. Using the TRAMP transgene and Rb and Nrf2 knockout murine models, we demonstrated that the loss of Nrf2 initiates a detrimental cascade of reduced GST expression, elevated ROS levels and ultimately DNA damage associated with tumorigenesis. Based on overwhelming data from clinical samples and the current functional analysis, we propose that the disruption of the Nrf2-antioxidant axis leads to increased oxidative stress and DNA damage in the initiation of cellular transformation in the prostate gland.

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Acknowledgements

We thank Jeffrey Johnson (University of Wisconsin, Madison, WI, USA) for providing us with founding Nrf2 heterozygous mice and NQO1-ARE luciferase plasimd. This study was supported by the grants from Department of Defense F013950 (DA Frohlich), National Institutes of Health 5T32 DK07758-05 and DK061488 (ML Day). National Institutes of Health 5T32 CA009674 (MT McCabe).

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Authors and Affiliations

  1. Department of Urology, UMCC, University of Michigan, Ann Arbor, MI, USA

    D A Frohlich

  2. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA

    M T McCabe

  3. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    R S Arnold

  4. Department of Urology, UMCC, University of Michigan, Ann Arbor, MI, USA

    M L Day

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  1. D A Frohlich
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Correspondence to M L Day.

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Frohlich, D., McCabe, M., Arnold, R. et al. The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis. Oncogene 27, 4353–4362 (2008). https://doi.org/10.1038/onc.2008.79

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