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J. Biol. Chem., Vol. 282, Issue 1, 809-820, January 5, 2007

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-Tocotrienol Inhibits Nuclear Factor-B Signaling Pathway through Inhibition of Receptor-interacting Protein and TAK1 Leading to Suppression of Antiapoptotic Gene Products and Potentiation of Apoptosis^*

Kwang Seok Ahn, Gautam Sethi, Koyamangalath Krishnan, and Bharat B. Aggarwal¹

From the Cytokine Research Section, Department of Experimental Therapeutics, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and Division of Hematology-Oncology, the Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee 37614-70622

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-B (NF-B) pathway has a central role in tumorigenesis, we investigated the effect of -tocotrienol on the NF-B pathway. Although-tocotrienol completely abolished tumor necrosis factor (TNF)-induced NF-B activation, a similar dose of -tocopherol had no effect. Besides TNF, -tocotrienol also abolished NF-B activation induced by phorbol myristate acetate, okadaic acid, lipopolysaccharide, cigarette smoke, interleukin-1, and epidermal growth factor. Constitutive NF-B activation expressed by certain tumor cells was also abrogated by -tocotrienol. Reducing agent had no effect on the -tocotrienol-induced down-regulation of NF-B. Mevalonate reversed the NF-B inhibitory effect of -tocotrienol, indicating the role of hydroxymethylglutaryl-CoA reductase. -Tocotrienol blocked TNF-induced phosphorylation and degradation of IB through the inhibition of IB kinase activation, thus leading to the suppression of the phosphorylation and nuclear translocation of p65. -Tocotrienol also suppressed NF-B-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, TAK1, receptor-interacting protein, NIK, and IB kinase but not that activated by p65. Additionally, the expressions of NF-B-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-tocotrienol. This correlated with potentiation of apoptosis induced by TNF, paclitaxel, and doxorubicin. Overall, our results demonstrate that -tocotrienol inhibited the NF-B activation pathway, leading to down-regulation of various gene products and potentiation of apoptosis.

Received for publication, October 26, 2006 , and in revised form, November 16, 2006.

^* This work was supported by a grant from the Clayton Foundation for Research (to B. B. A.), National Institutes of Health P01 Grant CA91844 on lung chemoprevention (to B. B. A.), and National Institutes of Health P50 Head and Neck SPORE Grant P50CA97007 (to B. B. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The Ransom Horne, Jr., Professor of Cancer Research. To whom correspondence should be addressed. Tel.: 713-792-3503/6459; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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