Abstract
We and others have previously described that the androgen-responsive human prostatic carcinoma cell line LNCaP is resistant to TRAIL and that TRAIL-mediated apoptosis in LNCaP is PI3K/Akt-dependent. In this study, we found that LNCaP remained resistant to treatment with TRAIL after androgen deprivation even in the presence of the PI3K/Akt pathway inhibitor wortmannin. This resistance was determined by failure to form the TRAIL-DISC and by decreased TRAIL-R1 and TRAIL-R2 levels after androgen deprivation; the capacity of TRAIL to induce DISC formation was completely restored in the presence of DHT. TRAIL and wortmannin together accelerated processing of caspase-8 on the DISC and apparently the release of caspase-8 from the DISC into the cytoplasm. Surprisingly, we found that wortmannin decreased the total amount of TRAIL-R1, but not TRAIL-R2, in the cells as well as the amount of TRAIL-R1 precipitated by TRAIL. Our data suggest that TRAIL-DISC formation and sensitivity to TRAIL treatment are androgen-dependent in LNCaP.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Androgens / metabolism*
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Androstadienes / pharmacology
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Blotting, Western
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Carrier Proteins / metabolism
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Caspase 8
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Caspase 9
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Caspases / metabolism*
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DNA Primers / chemistry
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Death Domain Receptor Signaling Adaptor Proteins
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Drug Resistance, Neoplasm
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Enzyme Inhibitors / pharmacology
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Fas-Associated Death Domain Protein
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Genes, Dominant
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Humans
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Male
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Membrane Glycoproteins / biosynthesis*
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Neoplasms, Hormone-Dependent / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Polymerase Chain Reaction
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Precipitin Tests
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / biosynthesis*
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction / drug effects*
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TNF-Related Apoptosis-Inducing Ligand
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / biosynthesis*
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Wortmannin
Substances
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Adaptor Proteins, Signal Transducing
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Androgens
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Androstadienes
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Apoptosis Regulatory Proteins
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Carrier Proteins
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DNA Primers
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Death Domain Receptor Signaling Adaptor Proteins
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Enzyme Inhibitors
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FADD protein, human
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Fas-Associated Death Domain Protein
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Membrane Glycoproteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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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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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases
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Wortmannin