TRAIL activates a caspase 9/7-dependent pathway in caspase 8/10-defective SK-N-SH neuroblastoma cells with two functional end points: induction of apoptosis and PGE2 release

Neoplasia. 2003 Sep-Oct;5(5):457-66. doi: 10.1016/s1476-5586(03)80048-9.

Abstract

Most neuroblastoma cell lines do not express apical caspases 8 and 10, which play a key role in mediating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity in a variety of malignant cell types. In this study, we demonstrated that TRAIL induced a moderate but significant increase of apoptosis in the caspase 8/10-deficient SK-N-SH neuroblastoma cell line, through activation of a novel caspase 9/7 pathway. Concomitant to the induction of apoptosis, TRAIL also promoted a significant increase of prostaglandin E2 (PGE2) release by SK-N-SH cells. Moreover, coadministration of TRAIL plus indomethacin, a pharmacological inhibitor of cyclooxygenase (COX), showed an additive effect on SK-N-SH cell death. In spite of the ability of TRAIL to promote the phosphorylation of both ERK1/2 and p38/MAPK, which have been involved in the control of COX expression/activity, neither PD98059 nor SB203580, pharmacological inhibitors of the ERK1/2 and p38/MAPK pathways, respectively, affected either PGE2 production or apoptosis induced by TRAIL. Finally, both induction of apoptosis and PGE2 release were completely abrogated by the broad caspase inhibitor z-VAD-fmk, suggesting that both biologic end points were regulated in SK-N-SH cells through a caspase 9/7-dependent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Blotting, Western
  • Caspase 10
  • Caspase 7
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Dinoprostone / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • MAP Kinase Signaling System
  • Membrane Glycoproteins / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Neuroblastoma / metabolism*
  • Phenotype
  • Phosphorylation
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Protein Isoforms
  • Pyridines / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Amino Acid Chloromethyl Ketones
  • Apoptosis Regulatory Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Membrane Glycoproteins
  • Protein Isoforms
  • Pyridines
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Prostaglandin-Endoperoxide Synthases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP7 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 10
  • Caspase 7
  • Caspase 8
  • Caspase 9
  • Caspases
  • CASP10 protein, human
  • Dinoprostone
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one