Abstract
Vitamin E derivative RRR-α-tocopherol ether-linked acetic acid analog (α-TEA) induces apoptosis in MCF-7 and HCC-1954 human breast cancer cells in a dose- and time-dependent manner. α-TEA induces increased levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor-5 (DR5) and decreased levels of antiapoptotic factor, cellular FLICE-like inhibitory protein (c-FLIP L). DR5/TRAIL induced apoptosis involves downregulation of c-FLIP (L), caspase-8 activation, activated proapoptotic mediators tBid and Bax, mitochondrial permeability transition, and activation of caspase-9. siRNA knockdown of either DR5 or TRAIL blocks the ability of α-TEA to enhance DR5 protein levels, downregulate c-FLIP(L) protein levels and induce apoptosis. Combination of α-TEA + TRAIL acts cooperatively to induce apoptosis, and increase DR5 and decrease c-FLIP (L) protein levels. siRNA knockdown of c-FLIP produces a low level of spontaneous apoptosis and enhances α-TEA- and TRAIL-induced apoptosis. Taken together, these studies show that α-TEA induces TRAIL/DR5 mitochondria-dependent apoptosis in human breast cancer cells, and that TRAIL/DR5-dependent increases in DR5 and decreases in c-FLIP expression are triggered by TRAIL or α-TEA treatments.
© 2010 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antioxidants / pharmacology
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Apoptosis / drug effects*
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Blotting, Western
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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CASP8 and FADD-Like Apoptosis Regulating Protein / antagonists & inhibitors
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
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Caspase 8 / metabolism
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Caspase 9 / metabolism
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Cytochromes c / metabolism
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Cytosol / drug effects
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Cytosol / metabolism
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mitochondria / drug effects
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Mitochondria / metabolism
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RNA, Messenger / genetics
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RNA, Small Interfering / pharmacology
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Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
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Tumor Cells, Cultured
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Vitamin E / analogs & derivatives
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alpha-Tocopherol / pharmacology*
Substances
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Antioxidants
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CASP8 and FADD-Like Apoptosis Regulating Protein
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RNA, Messenger
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RNA, Small Interfering
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RRR-alpha-tocopheryloxybutyrate
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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Vitamin E
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Cytochromes c
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Caspase 8
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Caspase 9
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alpha-Tocopherol