Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis.
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-kappaB (NF-kappaB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-kappaB activation found in certain tumor cells. Suppression of NF-kappaB activation occurred through the inhibition of phosphorylation and degradation of IkappaBalpha by the inhibition of IkappaB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-kappaB 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-kappaB-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)-alpha 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-kappaB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent.
Pandey
Manoj K
MK
Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Sung
Bokyung
B
Kunnumakkara
Ajaikumar B
AB
Sethi
Gautam
G
Chaturvedi
Madan M
MM
Aggarwal
Bharat B
BB
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001599:Berberine / Q000008:administration & dosage / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D019169:Jurkat Cells; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D002273:Carcinogens; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D001599:Berberine; D051550:I-kappa B Kinase; D003545:Cysteine