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

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.

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease

“…Furthermore, the expression of SOD1 in the lung, which is regulated by Nrf2 (ref. 26), was decreased by the PPE treatment, and subsequently restored by the concomitant treatment of animals with mepenzolate. This action of mepenzolate may also be involved in the observed decreased oxidative stress in vivo.…”

“…7c). It was reported that GST and its regulatory transcription factor, NF-E2-related factor 2 (Nrf2), in macrophages have an important role in the pathogenesis of COPD 25,26 . Therefore, we performed the Gene Set Enrichment Analysis using the custom gene set and confirmed that the downstream genes of Nrf2 (NFE2L2 target genes) were upregulated by the mepenzolate administration ( Supplementary Fig.…”

Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA

“…Constitutive CNC activity can be detrimental to reproduction and development (2,3), and tight regulation is thought to be achieved by controlling nuclear abundance, stability, posttranslational modification, and negative feedback (1,(3)(4)(5)(6)(7)(8). Mammalian Nrf2 is the best studied inducible CNC and is a popular therapeutic target for multiple age-and stress-related diseases (9)(10)(11). Nrf2 is regulated by a redox-sensitive ubiquitin ligase adaptor named Keap1 (5).…”

Antimutagenesis Studies: Where Have They Been and Where Are They Heading?

“…The transcription of many detoxifying enzymes is regulated through the antioxidant response element (ARE), whose transcription factor, Nrf2, is repressed under basal conditions by Keap1 (24,74,75). Dietz et al, 2008, described how extracts from the roots of Angelica sinensis, induced the detoxiˆcation enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) by alkylating Keap1.…”