Abstract
The underlying mechanisms of alpha-tocopheryl succinate (alpha-TOS)-mediated apoptosis are not understood in detail, although the redox-silent vitamin E analog is a potent apoptogen and anti-cancer agent. Our previous studies showed the important role of Fas signaling in apoptosis induced by the mitocan. The objective of the present study was to investigate whether apoptosis triggered by alpha-TOS in gastric carcinomas cells involves both mitochondria- and death receptor-dependent pathways. alpha-TOS induced apoptosis and mitochondrial permeability transition in a concentration- and time-dependent manner. As a consequence, cytochrome c and the apoptosis-inducing factor were released and caspases were activated. Bax was translocated from the cytosol to mitochondria and Bid was cleaved into its truncated form, tBid. Knocking down Bid by RNAi and Fas antisense oligodeoxynucleotides resulted in a decreased release and cleavage. The results imply that Bid may serve as a critical integrating factor of the death receptor and mitochondrial pathway in alpha-TOS-mediated apoptosis.
Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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BH3 Interacting Domain Death Agonist Protein / genetics
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BH3 Interacting Domain Death Agonist Protein / metabolism*
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Carcinoma / genetics
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Carcinoma / metabolism
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Carcinoma / pathology*
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Caspases / metabolism
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Cell Line, Tumor
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Cytochromes c / metabolism
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Dose-Response Relationship, Drug
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Enzyme Activation
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Humans
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondria / pathology
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Permeability Transition Pore
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Oligonucleotides, Antisense / metabolism
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Protein Transport
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RNA Interference
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Receptors, Death Domain / metabolism
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Signal Transduction / drug effects*
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology*
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Time Factors
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alpha-Tocopherol / pharmacology*
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bcl-2-Associated X Protein / metabolism
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fas Receptor / genetics
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fas Receptor / metabolism
Substances
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Antineoplastic Agents
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BAX protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Oligonucleotides, Antisense
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Receptors, Death Domain
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bcl-2-Associated X Protein
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fas Receptor
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Cytochromes c
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Caspases
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alpha-Tocopherol