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Increased Susceptibility of Nrf2 Knockout Mice to Colitis-Associated Colorectal Cancer

Authors' Affiliations: ¹ Center for Cancer Prevention Research and Departments of ² Pharmaceutics and ³ Chemical Biology (Susan Lehman Cullman Laboratory for Cancer Research), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; and ⁴ Department of Pathology, University of California, Irvine, California

Requests for reprints: Ah-Ng Kong, Center for Cancer Prevention Research, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854. Phone: 732-445-3831, ext. 228; Fax: 732-445-3134; E-mail: KongT{at}rci.rutgers.edu.

Abstract

The nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting various tissues against inflammation, which is a potential risk factor for colorectal and other cancers. Our previously published mouse model work showed that Nrf2 helps protect against dextran sulfate sodium (DSS)–induced colitis/inflammation, and others have shown that Nrf2 helps protect against inflammation-associated colorectal carcinogenesis (aberrant crypt foci). The present study extended these important earlier findings by exploring the role of Nrf2 in colitis-associated colorectal cancer in a mouse model involving azoxymethane/DSS–induced colorectal carcinogenesis in Nrf2 knockout mice. Azoxymethane/DSS–treated Nrf2 knockout mice had increased incidence, multiplicity, and size of all colorectal tumors, including adenomas, versus treated wild-type (WT) mice, and the proportion of tumors that were adenocarcinoma was much higher in knockout (80%) versus WT (29%) mice. Compared with WT mice, knockout mice also had increased markers of inflammation in tumor tissue (cyclooxygenase-2 and 5-lipoxygenase expressions and prostaglandin E₂ and leukotriene B₄ levels) and in inflamed colonic mucosa (nitrotyrosine expression), supporting the association of knockout mouse tumor formation with inflammation. The phase II detoxifying/antioxidant enzymes NAD(P)H-quinone reductase 1 and UDP-glucurosyltransferase 1A1 were elevated in the normal mucosa of WT, but not Nrf 2 knockout, mice treated with azoxymethane/DSS. Our findings show that Nrf2 plays a critical role in protecting against inflammation-associated colorectal cancer.

Commentary

Targeting Transcription Factors for Cancer Prevention—the Case of Nrf2

Nancy H. Colburn and Thomas W. Kensler
Cancer Prevention Research 2008 0: 1940-6207.CAPR-08-0025v1. [Abstract]