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

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.

• Authors: Si Qin, Fangming Deng, Weiguo Wu, Liwen Jiang, Takaaki Yamashiro, Satoshi Yano, De-Xing Hou
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 559 Pg. 53-61 (Oct 01 2014) ISSN: 1096-0384 [Electronic] United States
• PMID: 24704364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• 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, metabolism)
• Phosphorylation (drug effects)
• Protein Kinases (metabolism)
• Response Elements (drug effects)
• Transcription, Genetic (drug effects)
• Ubiquitination (drug effects)