Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis
Introduction
Tumor cells are monoclonal descendants of normal cells. They arise by a prolonged (often several decades) multistage process comprising the accumulation of damaging genetic and molecular changes that may lead to dysplastic and premalignant phenotypes and ultimately to invasion and metastasis. At any point in time, many cells in the body are believed to exist at some stage of this progression toward malignancy, but fortunately very few of these cells complete this journey and develop into clinically significant tumors. Therefore, for much of its temporal history, the development of cancer is a silent process: the stages of transformation and the locations of the abnormal cells are largely unknown. An important consequence of this sequence of events is that it presents multiple targets and a long time-frame in which to delay, interrupt, and even reverse the process of carcinogenesis. It is much easier to interrupt the carcinogenic process than to treat the established disease.
Since the number of new diagnoses of cancer is expected to double in the United States in the next 25–30 years, it is axiomatic that even dramatic advances in treatment cannot alleviate much of the enormous burden of cancer on individuals, on society, and on the medical care system. Similar crises are afflicting other parts of the world where, as in the US, populations are aging and mortality from cardiovascular diseases is declining. It is therefore mandatory to dedicate more effort to devising practical strategies for blocking carcinogenesis and thereby reducing the risk of cancer (Alberts et al., 1999).
The important role of xenobiotic metabolism in regulating carcinogenesis has been recognized for nearly 50 years (Conney et al., 1956; Miller and Miller, 1966). But only more recently has persuasive evidence accumulated that selective induction of protective phase 2 proteins is a highly effective, sufficient and probably quite safe strategy for reducing cellular susceptibility to electrophiles and reactive oxygen intermediates which are the principal causes of malignancy (Talalay et al., 1995; Kensler, 1997; Talalay (1999), Talalay (2000)).
Section snippets
Role of enzyme induction in protection against carcinogenesis: chemistry of phase 2 enzyme inducers
The induction of phase 2 enzymes involves enhanced gene expression resulting in increases in both mRNA and protein levels (Pearson et al., 1983; Benson et al., 1984; see reviews by Hayes et al., 1999; Hayes and McMahon, 2001). Inducers belong to two families: monofunctional inducers that elevate phase 2 enzymes selectively and bifunctional inducers that upregulate both phase 1 (principally cytochromes P450) and phase 2 enzymes (De Long et al., 1987; Prochaska and Talalay, 1988). Monofunctional
Evidence for the protective effects of phase 2 enzymes against oxidants and electrophiles: development of a bioassay for NAD(P)H:quinone reductase
Several complementary and compelling lines of evidence support the conclusion that phase 2 enzymes protect animals and their cells against the toxic and neoplastic effects of carcinogens (electrophiles and reactive oxygen intermediates), that these enzymes do not normally operate at maximal capacity, and that their induction is an effective strategy for further reducing vulnerability to carcinogens. Much of the evidence for this suggestion, which was first made nearly 25 years ago (Benson et al
Role of the antioxidant response element (ARE), the Nrf2 transcription factor, and the companion protein Keap1 in phase 2 gene regulation
Considerable insight has been obtained recently into the molecular details of how inducers signal enhanced transcription of phase 2 genes. Many phase 2 genes contain upstream promoter elements with the consensus sequence TGACnnnGC, designated the antioxidant response elements (ARE) (Rushmore et al., 1991; Jaiswal, 1994; Hayes and McMahon, 2001). Prominent among the transcription factors known to interact with AREs is Nrf2, which was shown by overexpression and by mobility shift assays to bind
Enhanced susceptibility to carcinogens and loss of protective efficacy of phase 2 enzyme inducers in mice deficient in the Nrf2 transcription factor
Recognition that the Nrf2 transcription factor is critical for the regulation of phase 2 genes (Venugopal and Jaiswal, 1996; Itoh et al., 1997) highlighted the issue of whether disruption of the nrf2 gene affected susceptibility to carcinogenesis and the response to chemoprotective inducers. Itoh and colleagues (1997) observed that the expression of glutathione transferase Ya and quinone reductase in wild-type (nrf2+/+)and heterozygous (nrf2+/−) mice was relatively normal and induced by the
Identity of the cellular sensor for phase 2 inducers
Very recent experiments have provided substantial insight into the details of the phase 2 gene induction mechanism (Dinkova-Kostova et al., 2002). The enormous chemical diversity of inducers suggested that a complementary cellular receptor was unlikely to be the sensor that recognized these inducers and switched on the enhanced transcription of phase 2 genes. The universal chemical reactivity of inducers with thiol groups, and the close correlation of inducer potencies with thiol reactivities
Summary
A growing body of evidence supports the view that induction of phase 2 enzymes is an effective strategy for lowering the susceptibility of animals and their cells to the carcinogenic effects of electrophiles and reactive oxygen intermediates, and thereby decreasing the risk of developing cancer. Many inducers of phase 2 genes are present in edible plants. They belong to a variety of chemical classes that have few apparent chemical similarities, and are therefore unlikely to react with a
Acknowledgements
Studies from the authors’ laboratory were supported by grants from the National Cancer Institute, Department of Health and Human Services (CA 94076 and CA 93780), the American Institute for Cancer Research, and the Cancer Research Foundation of America. It is a pleasure to acknowledge generous support from the Lewis B. and Dorothy Cullman Foundation, the Barbara Lubin Goldsmith Foundation, and the McMullan Family Fund.
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