Carcinogenesis Advance Access originally published online on September 28, 2006
Carcinogenesis 2007 28(3):639-647; doi:10.1093/carcin/bgl169
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Identification of kaempferol as an inhibitor of cigarette smoke-induced activation of the aryl hydrocarbon receptor and cell transformation
Department of Molecular and Biomedical Pharmacology, MS 305 University of Kentucky Medical Center KY 40536, USA
1 Graduate Center for Toxicology, University of Kentucky, Lexington KY 40536, USA
*To whom correspondence should be addressed at: Department of Molecular and Biomedical Pharmacology, UKMC MS-305, 800 Rose Street, Lexington, KY 40536-0084, USA. Tel: +1 859 323 1463; Fax: +1 859 323 1981; Email: hswan{at}uky.edu
The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which upon activation by its agonists, translocates into the nucleus and forms a dimer with ARNT (aryl hydrocarbon nuclear translocator). The AHR/ARNT dimer regulates the expression of its target genes by binding to DNA recognition elements termed dioxin responsive elements (DREs). Many AHR agonists, like the polyaromatic hydrocarbons and polyhalogenated hydrocarbons are known human carcinogens. Human exposure to these compounds is common due to their presence in air pollution and cigarette smoke. Interestingly, many dietary constituents that have chemo preventative properties have been found to also act as antagonists of the AHR pathway. Thus, a chemopreventive approach that may be effective in decreasing the incidences of many human cancers may involve a dietary regimen that includes a number of these naturally occurring AHR antagonists. With this idea in mind, we have assayed the ability of 15 flavonoids to inhibit AHR activated reporter activity and selected kaempferol for further analysis. Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. Using an in vitro paradigm of events that are thought to occur during cigarette-smoke-induced lung cancer, we found that kaempferol also inhibited the ability of cigarette smoke condensate to induce growth of immortalized lung epithelial (BEAS-2B) cells in soft agar. Taken together, these results illustrate the promise associated with the use of flavonoids, that inhibit both AHR signaling and the carcinogenic actions of AHR agonists, for chemopreventive purposes.
Abbreviations: AHR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon nuclear translocator; bHLH, basic helix–loop–helix; conDRE, consensus DRE; CSC, cigarette smoke condensate; DRE, dioxin responsive elements; MNF, 3'-methoxy-4'-nitroflavone; mutDRE, mutated DRE; TCDD, 2,3,7,8 tetrachlorodibenzo-p-dioxin.
Received September 15, 2006; revised August 22, 2006; accepted September 1, 2006.