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A strategy for cancer prevention: Stimulation of the Nrf2-ARE signaling pathway

¹ Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, New York and ² Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Yuesheng Zhang, Department of Chemoprevention, Roswell Park Cancer Institute, Science 711, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3097; Fax: 716-845-1144. E-mail: yuesheng.zhang{at}roswellpark.org

Many genes, with products involved in the protection of cells against carcinogens, oxidants, and other toxic chemicals, are under the transcriptional control of a simple DNA regulatory element [i.e., the antioxidant response element (ARE)]. One or more functional AREs have been confirmed or are believed to exist in the upstream region of many anticarcinogenic/antioxidant genes and have been shown to mediate the coordinate transcriptional up-regulation of these genes by many chemical agents [i.e., the ARE-mediated inducers]. There is strong evidence that increased expression of ARE-regulated genes inhibits cancer development. The signaling system leading to ARE activation has been partly elucidated, and nuclear factor erythroid 2–related factor 2 (Nrf2) has been identified as the key transcriptional factor that serves to transmit the inducer signal to ARE. It is now known that nuclear factor erythroid 2–related factor 2, which is normally sequestered in the cytoplasm by Kelch-like ECH-associated protein 1, dissociates from Kelch-like ECH-associated protein 1 on exposure to ARE-mediated inducers, translocates to the nucleus, complexes with other nuclear factors, and binds to ARE. Rapid and simple assays have been devised to identify chemical agents that can stimulate this signaling pathway. Moreover, many ARE-mediated inducers have been identified, and several of them have shown promising cancer preventive activity.

Received 3/ 5/04; revised 4/26/04; accepted 5/ 5/04.