Abstract
To determine if TRAIL-induced apoptosis in human prostate tumor cells was suppressed by bcl-2, we compared the levels of apoptosis induced by recombinant human TRAIL in pairs of isogenic cell lines that do or do not express bcl-2. Three human prostate tumor cell lines (PC3, DU145 and LNCaP) and their bcl-2-expressing counterparts were tested for their susceptibility to TRAIL. Cells were exposed to TRAIL in the presence of cycloheximide which acted as a sensitizer. Apoptosis was induced rapidly in PC3 and DU145 neo-control transfected cells, whereas induction in LNCaP required 24 h. All three cell line variants expressing bcl-2 were resistant to the apoptotic effects of TRAIL. Caspase 3 and 8 activation was also detected in the neo control cells after treatment with TRAIL, demonstrating the rapid activation of the caspase cascade similar to that seen with other death receptors. Bcl-2 overexpression in these cells blocked activation of these caspases, suggesting that bcl-2 expression of human cancer cells may be a critical factor in the therapeutic efficacy of TRAIL.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis Regulatory Proteins
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Apoptosis*
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BH3 Interacting Domain Death Agonist Protein
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / biosynthesis
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Carrier Proteins / metabolism
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Caspases / metabolism
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Cycloheximide / pharmacology
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Cytochrome c Group / metabolism
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Enzyme Activation
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Humans
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Intracellular Signaling Peptides and Proteins*
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Ligands
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Male
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / pharmacology*
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Cytochrome c Group
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Glycoproteins
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins
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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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Cycloheximide
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Caspases