TY - JOUR
T1 - Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms
AU - Qin, Si
AU - Deng, Fangming
AU - Wu, Weiguo
AU - Jiang, Liwen
AU - Yamashiro, Takaaki
AU - Yano, Satoshi
AU - Hou, De Xing
N1 - Funding Information:
This work was partially supported by National Natural Science Foundation of China ( 31101268 ) and Scientific Research Fund of Hunan Provincial Education Department ( 13B047 ) to S. Qin, and by Hunan Agriculture University Grant for 100 Intelligent Projects, and the fund of Scholar Research of Kagoshima University, Japan to D.X. Hou.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Baicalein, a major component of Scutellaria baicalensis Georgi (Huang Qin), is widely used in the traditional Chinese medicine. However, the mechanisms underlying cancer chemoprevention are still not clear. The present study aimed to clarify how baicalein modulate Nrf2/Keap1 system to exert its cytoprotection and cancer chemoprevention. In the upstream cellular signaling, baicalein stimulated the phosphorylation of MEK1/2, AKT and JNK1/2, which were demonstrated to be essential for baicalein-induced Nrf2 expression by their inhibitors. Immunoprecipitation with Nrf2 found that baicalein increased the amount of phosphorylated MEK1/2, AKT and JNK1/2 bound to Nrf2, and also stabilized Nrf2 protein by inhibiting the ubiquitination and proteasomal turnover of Nrf2. Simultaneously, baicalein down-regulated Keap1 by stimulating modification and degradation of Keap1 without affecting the dissociation of Keap1-Nrf2. Silencing Nrf2 using Nrf2 siRNA markedly reduced the ARE activity under both baseline and baicalein-induced conditions. Thus, baicalein positively modulate Nrf2/Keap1 system through both Keap1-independent and -dependent pathways. These finding provide an insight to understand the mechanisms of baicalein in cytoprotection and cancer chemoprevention.
AB - Baicalein, a major component of Scutellaria baicalensis Georgi (Huang Qin), is widely used in the traditional Chinese medicine. However, the mechanisms underlying cancer chemoprevention are still not clear. The present study aimed to clarify how baicalein modulate Nrf2/Keap1 system to exert its cytoprotection and cancer chemoprevention. In the upstream cellular signaling, baicalein stimulated the phosphorylation of MEK1/2, AKT and JNK1/2, which were demonstrated to be essential for baicalein-induced Nrf2 expression by their inhibitors. Immunoprecipitation with Nrf2 found that baicalein increased the amount of phosphorylated MEK1/2, AKT and JNK1/2 bound to Nrf2, and also stabilized Nrf2 protein by inhibiting the ubiquitination and proteasomal turnover of Nrf2. Simultaneously, baicalein down-regulated Keap1 by stimulating modification and degradation of Keap1 without affecting the dissociation of Keap1-Nrf2. Silencing Nrf2 using Nrf2 siRNA markedly reduced the ARE activity under both baseline and baicalein-induced conditions. Thus, baicalein positively modulate Nrf2/Keap1 system through both Keap1-independent and -dependent pathways. These finding provide an insight to understand the mechanisms of baicalein in cytoprotection and cancer chemoprevention.
KW - Baicalein
KW - Keap1 modification
KW - Nrf2 ubiquitination
KW - Nrf2/Keap1 system
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UR - http://www.scopus.com/inward/citedby.url?scp=84906790394&partnerID=8YFLogxK
U2 - 10.1016/j.abb.2014.03.011
DO - 10.1016/j.abb.2014.03.011
M3 - Article
C2 - 24704364
AN - SCOPUS:84906790394
SN - 0003-9861
VL - 559
SP - 53
EP - 61
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
ER -
