Abstract
RRR-alpha-tocopherol succinate (vitamin E succinate, VES) is a potent, selective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell culture and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK), but not p38, are critical mediators in VES-induced apoptosis of human breast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ERK1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of the substrate glutathione S-transferase-c-Jun and inhibited VES-induced apoptosis. Increased phosphorylation and transactivation activity of nuclear transcription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatments; however, only c-Jun and ATF-2 appear to be involved in VES-induced apoptosis based on antisense blockage experiments. Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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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Activating Transcription Factor 2
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Apoptosis / drug effects*
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Apoptosis / physiology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / enzymology*
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Breast Neoplasms / pathology
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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DNA-Binding Proteins*
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Enzyme Activation
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Humans
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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MAP Kinase Signaling System / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Mitogen-Activated Protein Kinases / physiology
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Oligonucleotides, Antisense / genetics
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Oligonucleotides, Antisense / pharmacology
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Phosphorylation / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Tocopherols
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptional Activation / drug effects
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Tumor Cells, Cultured
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Vitamin E / analogs & derivatives*
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Vitamin E / pharmacology*
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ets-Domain Protein Elk-1
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p38 Mitogen-Activated Protein Kinases
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Cyclic AMP Response Element-Binding Protein
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DNA-Binding Proteins
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ELK1 protein, human
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins
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Transcription Factors
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ets-Domain Protein Elk-1
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Vitamin E
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Tocopherols