title: Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis.
abstract: Unlike the tocopherols, the tocotrienols, also members of the vitamin E family, have an unsaturated isoprenoid side chain. In contrast to extensive studies on tocopherol, very little is known about tocotrienol. Because the nuclear factor-kappaB (NF-kappaB) pathway has a central role in tumorigenesis, we investigated the effect of gamma-tocotrienol on the NF-kappaB pathway. Although gamma-tocotrienol completely abolished tumor necrosis factor alpha (TNF)-induced NF-kappaB activation, a similar dose of gamma-tocopherol had no effect. Besides TNF, gamma-tocotrienol also abolished NF-kappaB activation induced by phorbol myristate acetate, okadaic acid, lipopolysaccharide, cigarette smoke, interleukin-1beta, and epidermal growth factor. Constitutive NF-kappaB activation expressed by certain tumor cells was also abrogated by gamma-tocotrienol. Reducing agent had no effect on the gamma-tocotrienol-induced down-regulation of NF-kappaB. Mevalonate reversed the NF-kappaB inhibitory effect of gamma-tocotrienol, indicating the role of hydroxymethylglutaryl-CoA reductase. Gamma-tocotrienol blocked TNF-induced phosphorylation and degradation of IkappaBalpha through the inhibition of IkappaBalpha kinase activation, thus leading to the suppression of the phosphorylation and nuclear translocation of p65. gamma-Tocotrienol also suppressed NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, TAK1, receptor-interacting protein, NIK, and IkappaBalpha kinase but not that activated by p65. Additionally, the expressions of NF-kappaB-regulated gene products associated with antiapoptosis (IAP1, IAP2, Bcl-xL, Bcl-2, cFLIP, XIAP, Bfl-1/A1, TRAF1, and Survivin), proliferation (cyclin D1, COX2, and c-Myc), invasion (MMP-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor) were down-regulated by gamma-tocotrienol. This correlated with potentiation of apoptosis induced by TNF, paclitaxel, and doxorubicin. Overall, our results demonstrate that gamma-tocotrienol inhibited the NF-kappaB activation pathway, leading to down-regulation of various gene products and potentiation of apoptosis.
authors.affiliation: Cytokine Research Section, Department of Experimental Therapeutics, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.forename: Koyamangalath
authors.initials: K
authors.lastname: Krishnan
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002839:Chromans; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D002839:Chromans; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D014810:Vitamin E; D000099151:MAP Kinase Kinase Kinase 7; C013649:plastochromanol 8