Berberine Modifies Cysteine 179 of IκBα Kinase, Suppresses Nuclear Factor-κB–Regulated Antiapoptotic Gene Products, and Potentiates Apoptosis
Open Access
- 1 July 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (13), 5370-5379
- https://doi.org/10.1158/0008-5472.can-08-0511
Abstract
Berberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-κB (NF-κB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-κB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-κB activation found in certain tumor cells. Suppression of NF-κB activation occurred through the inhibition of phosphorylation and degradation of IκBα by the inhibition of IκB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-κB reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK. Berberine also suppressed the expression of NF-κB–regulated gene products involved in antiapoptosis (Bcl-xL, Survivin, IAP1, IAP2, and cFLIP), proliferation (cyclin D1), inflammation (cyclooxygenase-2), and invasion (matrix metalloproteinase-9). Suppression of antiapoptotic gene products correlated with enhancement of apoptosis induced by tumor necrosis factor (TNF)-α and chemotherapeutic agents and with inhibition of TNF-induced cellular invasion. Overall, our results indicate that chemopreventive, apoptotic, and anti-inflammatory activities displayed by berberine may be mediated in part through the suppression of the NF-κB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent. [Cancer Res 2008;68(13):5370–9]Keywords
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This publication has 44 references indexed in Scilit:
- Effect of Berberine on Monocyte Chemotactic Protein-1 and Cytokine-Induced Neutrophil Chemoattractant-1 Expression in Rat Lipopolysaccharide-Induced UveitisOphthalmic Research, 2006
- Berberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3T3-L1 adipocyteExperimental & Molecular Medicine, 2006
- Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARγ pathwayBiochemical and Biophysical Research Communications, 2006
- Acetaldehyde-induced interleukin-1β and tumor necrosis factor-α production is inhibited by berberine through nuclear factor-κB signaling pathway in HepG2 cellsJournal of Biomedical Science, 2005
- The Aryl Hydrocarbon Receptor Predisposes Hepatocytes to Fas-Mediated ApoptosisMolecular Pharmacology, 2004
- From chemoprevention to chemotherapy: common targets and common goalsExpert Opinion on Investigational Drugs, 2004
- Herbimycin A Abrogates Nuclear Factor-κB Activation by Interacting Preferentially with the IκB Kinase β SubunitMolecular Pharmacology, 2004
- Effects of 13-alkyl-substituted berberine alkaloids on the expression of COX-II, TNF-α, iNOS, and IL-12 production in LPS-stimulated macrophagesLife Sciences, 2003
- Gold compound auranofin inhibits IκB kinase (IKK) by modifying Cys-179 of IKKβ subunitExperimental & Molecular Medicine, 2003
- NF-κB AND REL PROTEINS: Evolutionarily Conserved Mediators of Immune ResponsesAnnual Review of Immunology, 1998