Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-kappaB activation pathway.
Recent reports have indicated that honokiol can induce apoptosis, suppress tumor growth, and inhibit angiogenesis. In this report, we found that honokiol potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, suppressed TNF-induced tumor cell invasion, and inhibited RANKL-induced osteoclastogenesis, all of which are known to require nuclear factor-kappaB (NF-kappaB) activation. Honokiol suppressed NF-kappaB activation induced by a variety of inflammatory stimuli, and this suppression was not cell type specific. Further studies showed that honokiol blocked TNF-induced phosphorylation, ubiquitination, and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase and of Akt. This led to suppression of the phosphorylation and nuclear translocation of p65 and NF-kappaB-dependent reporter gene expression. Magnolol, a honokiol isomer, was equally active. The expression of NF-kappaB-regulated gene products involved in antiapoptosis (IAP1, IAP2, Bcl-x(L), Bcl-2, cFLIP, TRAF1, and survivin), proliferation (cyclin D1, cyclooxygenase-2, and c-myc), invasion (matrix metalloproteinase-9 and intercellular adhesion molecule-1), and angiogenesis (vascular endothelial growth factor) were also down-regulated by honokiol. Honokiol also down-regulated NF-kappaB activation in in vivo mouse dorsal skin model. Thus, overall, our results indicate that NF-kappaB and NF-kappaB-regulated gene expression inhibited by honokiol enhances apoptosis and suppresses osteoclastogenesis and invasion.
Ahn
Kwang Seok
KS
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Sethi
Gautam
G
Shishodia
Shishir
S
Sung
Bokyung
B
Arbiser
Jack L
JL
Aggarwal
Bharat B
BB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016259:Genes, myc; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D015394:Molecular Structure; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050863:Synaptotagmin I / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000498:Allyl Compounds; D010636:Phenols
D001713:Biphenyl Compounds; D002352:Carrier Proteins; D019938:Cyclin D1; D051546:Cyclooxygenase 2; D020672:I-kappa B Proteins; D017705:Lignans; D020780:Matrix Metalloproteinase 9; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050863:Synaptotagmin I; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C005498:magnolol; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C496540:PTGS2 protein, human