Activation of the Keap1-Nrf2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl reactive, small-molecule pharmacologic and food-based agents used in chemoprevention, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor Nrf2 to antioxidant response elements in the promoter regions of target genes. However, our recent work indicates that some of the protective effects may be mediated indirectly through cross-talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses through: (i) prevention of macromolecular damage through induction of antioxidative, anti-inflammatory and carcinogen detoxication genes;(ii) induction of macromolecular damage recognition, repair/removal systems;and (iii) activation of tissue repair/regeneration pathways. In this project we seek to use molecular, genetic and chemical approaches to test the hypothesis that chemoprotection mediated by Nrf2 reflects both activation of its direct target genes but importantly cross- talk with other adaptive response signaling networks affecting cell fate, such as Notch1. The overall goals of the proposed studies are two-fold: to assess the underlying mechanisms and consequences of pathway cross-talk and to assess the functional significance and possible untoward effects of chronic induction of the Nrf2 response in order to facilitate the identification and utilization of safe, efficacious chemopreventive agents.

Public Health Relevance

This research will examine the role of the transcription factor Nrf2 as a target for cancer chemoprevention by evaluating the contributions of cross-talk between this cytoprotective pathway and other signaling pathways influencing cell fate. Emphasis is placed on understanding the risks and benefits associated with long-term activation of Nrf2 signaling. Collectively, these studies will facilitate the identification and utilization of safe, efficacious chemopreventive agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094076-13
Application #
8635981
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Malone, Winfred F
Project Start
2001-12-21
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$361,998
Indirect Cost
$119,498
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yang, Li; Palliyaguru, Dushani L; Kensler, Thomas W (2016) Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane. Semin Oncol 43:146-53
Slocum, Stephen L; Skoko, John J; Wakabayashi, Nobunao et al. (2016) Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet. Arch Biochem Biophys 591:57-65
Wakabayashi, Nobunao; Chartoumpekis, Dionysios V; Kensler, Thomas W (2015) Crosstalk between Nrf2 and Notch signaling. Free Radic Biol Med 88:158-67
Chartoumpekis, Dionysios V; Palliyaguru, Dushani L; Wakabayashi, Nobunao et al. (2015) Notch intracellular domain overexpression in adipocytes confers lipodystrophy in mice. Mol Metab 4:543-50
Zhang, Yongshu; Xia, Jixiang; Li, Qinglin et al. (2014) NRF2/long noncoding RNA ROR signaling regulates mammary stem cell expansion and protects against estrogen genotoxicity. J Biol Chem 289:31310-8
Johnson, Natalie M; Egner, Patricia A; Baxter, Victoria K et al. (2014) Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold. Cancer Prev Res (Phila) 7:658-65
Wakabayashi, Nobunao; Skoko, John J; Chartoumpekis, Dionysios V et al. (2014) Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling. Mol Cell Biol 34:653-63
Kensler, Kevin H; Slocum, Stephen L; Chartoumpekis, Dionysios V et al. (2014) Genetic or pharmacologic activation of Nrf2 signaling fails to protect against aflatoxin genotoxicity in hypersensitive GSTA3 knockout mice. Toxicol Sci 139:293-300
Skoko, John J; Wakabayashi, Nobunao; Noda, Kentaro et al. (2014) Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity. Toxicol Sci 141:112-9
Kensler, Thomas W; Egner, Patricia A; Agyeman, Abena S et al. (2013) Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane. Top Curr Chem 329:163-77

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