Pharmaceutical Research

, Volume 27, Issue 6, pp 999–1013 | Cite as

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

Expert Review

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.

KEY WORDS

anti-inflammation chemoprevention chemopreventive agents inflammation Keap1 Nrf2 redox signaling 

Notes

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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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.College of PharmacySeoul National UniversitySeoulSouth Korea
  2. 2.Department of Molecular Medicine and Biopharmaceutical Sciences and Graduate School of Convergence Science and TechnologySeoul National UniversitySeoulSouth Korea

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