Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery.
Avicins are proapoptotic and anti-inflammatory triterpene electrophiles isolated from an Australian desert tree, Acacia victoriae. The presence of two alpha,beta unsaturated carbonyl groups (Michael reaction sites) in the side chain of the avicin molecule prompted us to study its effects on NF-E2-related factor 2 (Nrf2), a redox-regulated transcription factor that controls the expression of a battery of detoxification and antioxidant proteins via its binding to antioxidant response element (ARE). Avicin D-treated Hep G2 cells showed translocation of Nrf2 into the nucleus and a time-dependent increase in ARE activity. These properties were sensitive to DTT, suggesting that avicins affect one or more critical cysteine residues, probably on the Keap1 molecule. Downstream of ARE, an activation of a battery of stress-induced proteins occurred. The implications of these findings were evaluated in vivo in mouse skin exposed to an ancient stressor, UV light. Avicins inhibited epidermal hyperplasia, reduced p53 mutation, enhanced apoptosis, decreased generation of 8-hydroxy-2'-deoxyguanosine, and enhanced expression of NADPH:quinone oxidoreductase 1 and heme oxygenase-1. These data, combined with our earlier published work, demonstrate that avicins represent a new class of plant stress metabolites capable of activating stress adaptation and suppressing proinflammatory components of the innate immune system in human cells by redox regulation. The relevance for treatment of clinical diseases in which stress responses are dysfunctional or deficient is discussed.
Haridas
Valsala
V
Department of Molecular Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Hanausek
Margaret
M
Nishimura
Goshi
G
Soehnge
Holly
H
Gaikwad
Amos
A
Narog
Maciej
M
Spears
Erick
E
Zoltaszek
Robert
R
Walaszek
Zbigniew
Z
Gutterman
Jordan U
JU
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular; D004229:Dithiothreitol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008113:Liver Neoplasms; D011994:Recombinant Proteins / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D014162:Transfection; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011994:Recombinant Proteins; D012503:Saponins; D014315:Triterpenes; C478445:avicin D; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D005978:Glutathione; D004229:Dithiothreitol