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Nrf2-Keap1 Signaling as a Potential Target for Chemoprevention of Inflammation-Associated Carcinogenesis

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ABSTRACT

Persistent inflammatory tissue damage is causally associated with each stage of carcinogenesis. Inflammation-induced generation of reactive oxygen species, reactive nitrogen species, and other reactive species not only cause DNA damage and subsequently mutations, but also stimulate proliferation of initiated cells and even metastasis and angiogenesis. Induction of cellular cytoprotective enzymes (e.g., heme oxygenase-1, NAD(P)H:quinone oxidoreductase, superoxide dismutase, glutathione-S-transferase, etc.) has been shown to mitigate aforementioned events implicated in inflammation-induced carcinogenesis. A unique feature of genes encoding these cytoprotective enzymes is the presence of a cis-acting element, known as antioxidant response element (ARE) or electrophile response element (EpRE), in their promoter region. A stress-responsive transcription factor, nuclear factor erythroid-2-related factor-2 (Nrf2), initially recognized as a key transcriptional regulator of various cytoprotective enzymes, is known to play a pivotal role in cellular defense against inflammatory injuries. Activation of Nrf2 involves its release from the cytosolic repressor Kelch-like ECH-associated protein-1 (Keap1) and subsequent stabilization and nuclear localization for ARE/EpRE binding. Genetic or pharmacologic inactivation of Nrf2 has been shown to abolish cytoprotective capability and to aggravate experimentally induced inflammatory injuries. Thus, Nrf2-mediated cytoprotective gene induction is an effective strategy for the chemoprevention of inflammation-associated carcinogenesis.

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ACKNOWLEDGEMENTS

This work was supported by the grants for 21C Frontier Functional Human Genome Project (Grant Number FG07-21-21) and the Innovative Drug Research Center (R11-2007-107-01002-0) from National Research Foundation, the Ministry of Education, Science and Technology, Republic of Korea.

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  1. College of Pharmacy, Seoul National University, 599 Kwanak-ro, Kwanak-ku, Seoul, 151-742, South Korea

    Joydeb Kumar Kundu & Young-Joon Surh

  2. Department of Molecular Medicine and Biopharmaceutical Sciences and Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 151-742, South Korea

    Young-Joon Surh

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  1. Joydeb Kumar Kundu
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Kundu, J.K., Surh, YJ. Nrf2-Keap1 Signaling as a Potential Target for Chemoprevention of Inflammation-Associated Carcinogenesis. Pharm Res 27, 999–1013 (2010). https://doi.org/10.1007/s11095-010-0096-8

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  • DOI: https://doi.org/10.1007/s11095-010-0096-8

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