Carcinogenesis Advance Access originally published online on June 29, 2007
Carcinogenesis 2007 28(11):2398-2403; doi:10.1093/carcin/bgm146
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Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis
1 Department of Urology, Institute of Clinical Medicine
2 Center for Tsukuba Advanced Research Alliance (TARA), Institute of Basic Medical Sciences and Japan Science and Technology Agency (JST)-Exploratory Research for Advanced Technology (ERATO) Environmental Response Project
3 Institute of Community Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan
4 Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611-3008, USA
5 Institute of Biological Pharmacy, Gifu Pharmaceutical University, Mitahora-higashi 5-6-1, Gifu 502-8585, Japan
* To whom correspondence should be addressed. Tel: +81 298 53 6158; Fax: +81 298 53 7318; Email: masi{at}tara.tsukuba.ac.jp
Correspondence may also be addressed to Ken Itoh. Tel: +81 172 39 5158; Fax: +81 172 39 5157;Email: itohk{at}cc.hirosaki-u.ac.jp
Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2), a transcription factor that regulates inducible expression of detoxifying enzymes, is critical in preventing N-nitrosobutyl(4-hydroxybutyl)amine (BBN)-induced urinary bladder carcinogenesis. To explore whether Nrf2 and the tumor suppressor p53 cooperatively act in tumor prevention, we investigated the susceptibility of Nrf2–/–::p53+/– mice to BBN-induced urinary bladder carcinogenesis. The incidence of BBN-induced urinary bladder carcinoma was 63.0% in Nrf2–/– mice (P = 0.115), 75.8% in p53+/– mice (P < 0.01) and 89.6% in Nrf2–/–::p53+/– mice (P < 0.01) compared with 37.9% in wild-type. Higher incidence of carcinoma was observed in Nrf2–/–::p53+/– mice when compared with either Nrf2–/– (P < 0.01) or p53+/– mice (P = 0.382). Similarly, muscular invasive carcinoma incidence was higher in Nrf2–/–::p53+/– mice (62.0%) than either wild-type (6.9%, P < 0.01), p53+/– (38.0%, P = 0.110) or Nrf2–/– mice (3.7%, P < 0.01). Furthermore, urinary concentrations of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN, were only increased when Nrf2 but not p53 was disrupted. These results demonstrate that tumor susceptibility is synergistically exacerbated in Nrf2–/–::p53+/– mice due to poor detoxification and accelerated proliferation in comparison with either single mutant alone. BBN administration increased p53-mediated expression of p21, Mdm2 and Bax, and the inducible expression of p21 was significantly enhanced in Nrf2–/– mice. Conversely, modest increases in NAD(P)H dehydrogenase, quinone 1 (NQO1) and uridine diphosphate (UDP) glucuronosyltransferase 1A6 (UGT1A6) expression were observed in p53+/– compared with those of wild-type mice after BBN exposure. These results thus reveal potential interactions between p53 and Nrf2 and their gene batteries, and indicate that both factors cooperatively contribute to tumor prevention.
Abbreviations: BBN, N-nitrosobutyl(4-hydroxybutyl)amine; BCPN, N-nitrosobutyl(3-carboxypropyl)amine; mRNA, messenger RNA
Received February 1, 2007; revised May 24, 2007; accepted June 18, 2007.
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