Carcinogenesis Advance Access published online on April 21, 2009
Carcinogenesis, doi:10.1093/carcin/bgp100
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Genetic versus Chemoprotective Activation of Nrf2 Signaling: Overlapping yet Distinct Gene Expression Profiles between Keap1 Knockout and Triterpenoid Treated Mice
1 Johns Hopkins University, Baltimore, Maryland
2 University of Memphis, Memphis, Tennessee
3 General Electric Company, Global Research Center, Niskayuna, New York
4 Tohoku University Graduate School of Medicine and ERATO Environmental Response Project, Sendai, Japan
5 Dartmouth Medical School, Hanover, New Hampshire
Corresponding author: Dr. Thomas Kensler, SPH Rm E7541, 615 N. Wolfe St. Baltimore, Maryland 21205, Telephone: 410-955-1292, Fax: 410-955-0116, tkensler{at}jhsph.edu
Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although inactivating mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. The results show that genetic and pharmacologic activation of Nrf2 signaling modulates pathways beyond detoxication and cytoprotection, with the largest cluster of genes associated with lipid metabolism. Genetic activation of Nrf2 results in much larger numbers of detoxication and lipid metabolism gene changes. Additionally, analysis of pharmacologic activation suggests that Nrf2 is the primary mediator of CDDO-Im activity, though other cell signaling targets are also modulated following an oral dose of 30 µmol/kg.
Key Words: Nrf2 • Keap1 • chemoprevention • triterpenoid • CDDO-Im
Received March 13, 2009; revised April 13, 2009; accepted April 15, 2009.