This Article Full Text (Online First [PDF]) Related Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Colburn, N. H. Articles by Kensler, T. W. PubMed Articles by Colburn, N. H. Articles by Kensler, T. W. Related Collections Perspective Key Article

Targeting Transcription Factors for Cancer Prevention—the Case of Nrf2

Authors' Affiliations: ¹ Laboratory of Cancer Prevention, National Cancer Institute, Frederick, Maryland and ² Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

Requests for reprints: Nancy H. Colburn, Laboratory of Cancer Prevention, National Cancer Institute, Building 576, Room 101, Frederick, MD 21702-1201. Phone: 301-846-1342; Fax: 301-846-6907; E-mail: Colburn{at}ncifcrf.gov.

Abstract

NF-E2-related factor 2 (Nrf2) is one of several transcription factors that are altered in human cancer and that modulate susceptibility to carcinogenesis in mouse models (1–3). Nrf2 up-regulates transcription of a number of oxidant and electrophile detoxication genes through an antioxidant response element present in their transcriptional promoters. In this issue of the journal, Khor et al. (4) follow up their own and others' previous findings that Nrf2 protects against dextran sodium sulfate–induced colitis, inflammation, and aberrant crypt foci with a study now showing that tumor incidence, multiplicity, size, and stage of progression are increased in Nrf2-deficient mice in an azoxymethane-dextran sodium sulfate colon carcinogenesis model. Expressions of the proinflammatory genes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) and their products prostaglandin E₂ and leukotriene B₄ were increased in tumors induced in the knockout mice compared with wild-type tumors and with normal mucosa. Induction of prototypic protective enzymes UDP-glucuronosyl transferase 1A and NAD(P)H:quinone oxidoreductase 1 following azoxymethane-dextran sodium sulfate failed to occur in Nrf2-deficient mice. Although the association between chronic inflammation and cancer has been noted for several cancer sites including liver, pancreas, stomach, bladder, and colon, the molecular basis for this association is not well understood. Khor et al. now implicate activation of pro-oxidant enzymes such as COX-2 and 5-LOX and lowered expression of antioxidant enzymes such as NAD(P)H:quinone oxidoreductase 1 as likely mediators of the inflammation-associated colon tumor promotion and progression in Nrf2-deficient mice. This suggests that activation of Nrf2 or Nrf2 signaling might be a promising strategy for prevention of inflammation-associated cancer.

Key Article

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

Tin Oo Khor, Mou-Tuan Huang, Auemduan Prawan, Yue Liu, Xingpei Hao, Siwang Yu, William Ka Lung Cheung, Jefferson Y. Chan, Bandaru S. Reddy, Chung S. Yang, and Ah-Ng Kong
Cancer Prevention Research 2008 0: 1940-6207.CAPR-08-0028v1. [Abstract]