Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms

Si Qin; Fangming Deng; Weiguo Wu; Liwen Jiang; Takaaki Yamashiro; Satoshi Yano; De-Xing Hou

doi:10.1016/j.abb.2014.03.011

Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms

Arch Biochem Biophys. 2014 Oct 1:559:53-61. doi: 10.1016/j.abb.2014.03.011. Epub 2014 Apr 3.

Authors

Si Qin¹, Fangming Deng², Weiguo Wu², Liwen Jiang², Takaaki Yamashiro³, Satoshi Yano³, De-Xing Hou⁴

Affiliations

¹ The Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China; Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima, Japan.
² The Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China.
³ Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima, Japan.
⁴ The Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China; Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima, Japan; United Graduate School of Agricultural Sciences, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-0065, Japan. Electronic address: hou@chem.agri.kagoshima-u.ac.jp.

PMID: 24704364
DOI: 10.1016/j.abb.2014.03.011

Abstract

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.

Keywords: Baicalein; Keap1 modification; Nrf2 ubiquitination; Nrf2/Keap1 system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antioxidants / metabolism
Chemoprevention
Cytoprotection / drug effects
Flavanones / pharmacology*
Gene Expression Regulation / drug effects
Hep G2 Cells
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Kelch-Like ECH-Associated Protein 1
NAD(P)H Dehydrogenase (Quinone) / genetics
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Phosphorylation / drug effects
Protein Kinases / metabolism
Response Elements / drug effects
Transcription, Genetic / drug effects
Ubiquitination / drug effects

Substances

Antioxidants
Flavanones
Intracellular Signaling Peptides and Proteins
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
NFE2L2 protein, human
baicalein
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, human
Protein Kinases