Abstract
In a variety of malignant cells Prostate-apoptosis-response-gene-4 (Par-4) exhibits a pro-apoptotic influence sensitizing these cells to apoptosis-inducing agents by downregulating expression of Bcl-2. Considering the crucial role of Bcl-2 in the development of chemoresistance of acute myeloid leukemia (AML) cells, we here assessed the potential of Par-4 to down-regulate Bcl-2 and to induce apoptosis in the erythroleukemic cell line HEL. Testing a potential pro-apoptotic role of Par-4 upon incubation with various conventional chemotherapeutic drugs, novel agents such as the signal transduction inhibitor STI 571 and the histone deacetylase (HDAC)- inhibitor trichostatin A (TSA), as well as with the experimental substances Fas and TRAIL, we provide evidence that in the erythroleukemic cell line HEL expression of Par-4 is not sufficient to sensitize to any of these pro-apoptotic stimuli. We further demonstrate that--in contrast to previous reports in non-AML cells--Par-4 expression in HEL cells leads to an upregulation of Bcl-2. Moreover, Par-4-positive HEL cells exhibit a decreased level of the proapoptotic protein Bax as compared to Par-4- negative cells. In addition, Par-4 increases the expression of Daxx--whose downregulation is associated with augmented chemosensitivity--as well as expression of the procaspases-8, -9 and -10, whereas the levels of the procaspases-3 and -7 remain unaltered. In conclusion we here demonstrate that in the erythroleukemic cell line HEL--in contrast to other cell types Par-4 fails to promote apoptosis and outline the underlying molecular mechanisms.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal / pharmacology
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Benzamides
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Caspase 10
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Caspase 8
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Caspase 9
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Caspases / biosynthesis
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Caspases / genetics
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism*
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Cell Line, Tumor / pathology
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Co-Repressor Proteins
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Enzyme Precursors / biosynthesis
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Enzyme Precursors / genetics
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Gene Expression Regulation, Leukemic* / drug effects
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Genes, bcl-2*
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Histone Deacetylase Inhibitors
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Humans
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Hydroxamic Acids / pharmacology
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Imatinib Mesylate
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Intracellular Signaling Peptides and Proteins*
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Leukemia, Erythroblastic, Acute / genetics
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Leukemia, Erythroblastic, Acute / pathology*
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Membrane Glycoproteins / agonists
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Molecular Chaperones
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Piperazines / pharmacology
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Pyrimidines / pharmacology
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TNF-Related Apoptosis-Inducing Ligand
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Transfection
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Tumor Necrosis Factor-alpha / agonists
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bcl-2-Associated X Protein
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fas Receptor / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BAX protein, human
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Benzamides
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Carrier Proteins
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Co-Repressor Proteins
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DAXX protein, human
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Enzyme Precursors
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Molecular Chaperones
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Neoplasm Proteins
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Nuclear Proteins
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrimidines
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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bcl-2-Associated X Protein
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fas Receptor
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prostate apoptosis response-4 protein
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trichostatin A
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Imatinib Mesylate
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CASP8 protein, human
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CASP9 protein, human
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Caspase 10
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Caspase 8
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Caspase 9
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Caspases
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CASP10 protein, human