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

• Published in: Archives of biochemistry and biophysics 2014-10, Vol.559, p.53-61
• Main Authors: Qin, Si, Deng, Fangming, Wu, Weiguo, Jiang, Liwen, Yamashiro, Takaaki, Yano, Satoshi, Hou, De-Xing
• Format: Article
• Language: English
• Subjects: Antioxidants - metabolism; Baicalein; Chemoprevention; Cytoprotection - drug effects; Flavanones - pharmacology; Gene Expression Regulation - drug effects; Hep G2 Cells; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Keap1 modification; Kelch-Like ECH-Associated Protein 1; NAD(P)H Dehydrogenase (Quinone) - genetics; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2 ubiquitination; Nrf2/Keap1 system; Phosphorylation - drug effects; Protein Kinases - metabolism; Response Elements - drug effects; Transcription, Genetic - drug effects; Ubiquitination - drug effects
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2014.03.011

[Display omitted] •Modulation of Nrf2/Keap1 system by baicalein was investigated in HepG2 cells.•Baicalein increases Nrf2 mRNA by activating upstream protein kinase.•Baicalein also stabilizes Nrf2 by inhibiting the ubiquitination and degradation.•Baicalein downregulates Keap1 by stimulating its modification and degradation.•Baicalein exerts cytoprotection by both downregulating Keap1and upregulating Nrf2. 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.