Abstract
Most tumor cells are sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis but sparing to normal cells, thus providing therapeutic potential for clinical use. Some tumor cells are resistant to TRAIL-induced cell death while the sensitivity could be recruited with the existence of some chemical agents. In this study, human prostatic cancer cell line LNCaP was found to be resistant to TRAIL-induced apoptosis while it could be restored to TRAIL sensitivity with combination treatment of low concentration of doxorubicin. TRAIL receptor-1 (DR4) and TRAIL receptor-2 (DR5) were upregulated under the treatment of doxorubicin and verified to be responsible for TRAIL-mediated signal transduction. Furthermore, caspase-8 and caspase-3 were activated and drove their autocleavage into programmed cell death. Interestingly, apoptosis-inhibitory protein c-FLIP, but not Bcl-2 and XIAP was downregulated after doxorubicin treatment. Taken together, these findings suggested that the pathway of cell apoptosis induced by TRAIL was intact but under negative control. Subtoxic concentration of doxorubicin effectively boosted TRAIL sensitivity via depletion of antiapoptotic protein. These findings support the new strategies for killing tumors with TRAIL and chemical agents.
MeSH terms
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Antibiotics, Antineoplastic / administration & dosage*
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Antibiotics, Antineoplastic / metabolism
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Antineoplastic Agents / pharmacology
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis*
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Blotting, Western
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Caspase 3
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Caspase 8
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Caspases / biosynthesis
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Cell Line, Tumor
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Cell Survival
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Down-Regulation
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Doxorubicin / administration & dosage*
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Doxorubicin / metabolism
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Flow Cytometry
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Gene Expression Regulation, Neoplastic*
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Membrane Glycoproteins / metabolism*
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Models, Biological
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / biosynthesis
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Signal Transduction
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TNF-Related Apoptosis-Inducing Ligand
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Time Factors
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Tumor Necrosis Factor-alpha / metabolism*
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Up-Regulation
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10A protein, human
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TNFRSF10B protein, human
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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X-Linked Inhibitor of Apoptosis Protein
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Doxorubicin
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CASP3 protein, human
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CASP8 protein, human
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Caspase 3
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Caspase 8
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Caspases