Nrf2 Is Essential for the Chemopreventive Efficacy of Oltipraz against Urinary Bladder Carcinogenesis

Abstract

The induction of phase 2 detoxifying enzymes, such as UDP-glucuronosyltransferases (UGTs), in response to an array of naturally occurring and synthetic agents, such as oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione), provides an effective means of protection against a variety of carcinogens. Transcription factor Nrf2 is an essential regulator of the inducible expression of detoxifying enzyme genes by chemopreventive agents. In this study, we investigated in Nrf2-deficient mice the susceptibility to the urinary bladder-specific carcinogen N-nitrosobutyl(4-hydroxybutyl)amine (BBN) and the chemopreventive efficacy of oltipraz. The incidence of urinary bladder carcinoma by BBN was significantly higher in Nrf2 ؊/؊ mice than in wild-type mice; invasive carcinoma was found in 24.0 and 38.5% of wild-type and Nrf2 ؊/؊ mice, respectively. Oltipraz induced the phase 2 enzymes responsible for BBN detoxification in the liver and urinary bladder in an Nrf2-dependent manner. As expected, therefore, oltipraz decreased the incidence of urinary bladder carcinoma by BBN in wild-type mice but had little effect in Nrf2 ؊/؊ mice. In wild-type mouse liver, oltipraz significantly induced BBN glucuronidation and decreased the urinary concentration of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN. Importantly, BBN was found to suppress the expression of UGT1A specifically in the urinary bladder. This suppression was counteracted by oltipraz in wild-type mice but not in Nrf2 ؊/؊ mice. These results show that Nrf2 and its downstream target genes are responsible for BBN detoxification. Furthermore, oltipraz prevents carcinogenesis by BBN by enhancing detoxification of this carcinogen in the liver and urinary bladder.

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

“…The transcription factor Nrf2 mediates gene induction of protective phase-2 detoxifying enzymes and its activation by thiol-active compounds, found in a variety of natural foods and dietary supplements, has been advocated as a means to prevent cancer (3,4). By contrast, Nrf2-deficient mice are highly susceptible to chemically induced carcinogenesis of multiple organs (5,6). Under normal, nonstressed circumstances, low cellular concentrations of Nrf2 are maintained by proteasomal degradation, through a Keap1-Cullin 3-Roc1-dependent mechanism in which Keap1 serves as the substrate adaptor subunit in the E3 holoenzyme.…”

Cancer, Oxidative Stress, and Metastasis

“…Prdx6 overexpression in keratinocytes can reduce the initiation of skin tumors, but once they arise, cancer progression is accelerated by Prdx6 overexpression (Rolfs et al 2013). Similarly, NRF2 confers resistance to chemical carcinogens but also promotes cancer progression by protecting cancer cells from oxidative stress and DNA damage (Ramos-Gomez et al 2001;Iida et al 2004;Hayes and McMahon 2006;Hu et al 2006;Xu et al 2006;Ma 2013;Satoh et al 2013). Increased NRF2 expression in human cancers correlates with a poor prognosis (Moon and Giaccia 2015).…”

Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1

“…Nrf2-deficient mice are prone to both chemical toxicity and tumorigenesis (15)(16)(17)(18). Recently, somatic mutations of human KEAP1 and NRF2 have also been identified in various types of cancers.…”