Abstract
The orphan nuclear receptor TR3/Nur77 has emerged as a viable candidate in the coordinate regulation of cell proliferation and apoptosis, essential for maintaining normal architecture in rapidly renewing tissues such as the colonic mucosa. TR3 induces apoptosis in a number of cell lineages exposed to proapoptotic stimuli by directly targeting the mitochondria, inducing cytochrome c release. Here we report a distinctly different mechanism of TR3-mediated apoptosis in colon cancer cells. Nucleus-to-cytoplasm translocation of a green fluorescent protein-TR3 construct, but not its direct mitochondrial targeting, was associated with apoptosis induced by the short-chain fatty acid, butyrate. Similar results were observed for the nonsteroidal anti-inflammatory drug, sulindac, and the chemotherapeutic drug, 5-fluorouracil. A mutant TR3 construct lacking DNA-binding ability exerted a potent proapoptotic effect in colon cancer cells that was associated with cytochrome c release, an action dependent upon cytoplasmic localization of the construct, but, again, not its direct mitochondrial targeting. We identified a potential role for BAX recruitment to the mitochondria, secondary to cytoplasmic translocation of TR3, in inducing cytochrome c release and in mediating apoptosis. Therefore, TR3 translocation from the nucleus may initiate the apoptotic cascade in colon cancer cells by stimulating other cytosolic proapoptotic molecules to associate with mitochondria.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Butyrates / pharmacology
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Cell Nucleus / metabolism
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology*
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Cytochrome c Group / metabolism
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DNA, Neoplasm / metabolism
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Green Fluorescent Proteins
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Humans
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Luminescent Proteins / biosynthesis
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Mitochondria / metabolism
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Mitochondria / physiology
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-bcl-2*
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Receptors, Steroid / biosynthesis
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism
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Receptors, Steroid / physiology*
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Receptors, Thyroid Hormone / biosynthesis
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Receptors, Thyroid Hormone / genetics
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Receptors, Thyroid Hormone / metabolism
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Receptors, Thyroid Hormone / physiology*
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Tetradecanoylphorbol Acetate / pharmacology
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Transfection
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Tumor Cells, Cultured
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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Butyrates
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Cytochrome c Group
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DNA, Neoplasm
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Luminescent Proteins
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NR4A1 protein, human
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Steroid
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Receptors, Thyroid Hormone
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Recombinant Fusion Proteins
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bcl-2-Associated X Protein
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Green Fluorescent Proteins
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Tetradecanoylphorbol Acetate