TRAIL-DISC formation is androgen-dependent in the human prostatic carcinoma cell line LNCaP

Cancer Biol Ther. 2002 Nov-Dec;1(6):631-7. doi: 10.4161/cbt.311.

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

  • Adaptor Proteins, Signal Transducing*
  • Androgens / metabolism*
  • Androstadienes / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • DNA Primers / chemistry
  • Death Domain Receptor Signaling Adaptor Proteins
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology
  • Fas-Associated Death Domain Protein
  • Genes, Dominant
  • Humans
  • Male
  • Membrane Glycoproteins / biosynthesis*
  • Neoplasms, Hormone-Dependent / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Polymerase Chain Reaction
  • Precipitin Tests
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / biosynthesis*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Signal Transduction / drug effects*
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Wortmannin

Substances

  • Adaptor Proteins, Signal Transducing
  • Androgens
  • Androstadienes
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DNA Primers
  • Death Domain Receptor Signaling Adaptor Proteins
  • Enzyme Inhibitors
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Membrane Glycoproteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases
  • Wortmannin