Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Apoptosis. 2007 Jan;12(1):211-23. doi: 10.1007/s10495-006-0528-4.


Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) shows promise as a chemotherapeutic agent. However, many human cancer cells are resistant to killing by TRAIL. We have previously demonstrated that reovirus infection increases the susceptibility of human lung (H157) and breast (ZR75-1) cancer cell lines to TRAIL-induced apoptosis. We now show that reovirus also increases the susceptibility of human ovarian cancer cell lines (OVCAR3, PA-1 and SKOV-3) to TRAIL-induced apoptosis. Reovirus-induced increases in susceptibility of OVCAR3 cells to TRAIL require virus uncoating and involve increased activation of caspases 3 and 8. Reovirus infection results in the down-regulation of cFLIP (cellular FLICE inhibitory protein) in OVCAR3 cells. Down-regulation of cFLIP following treatment of OVCAR3 cells with antisense cFLIP oligonucleotides or PI3 kinase inhibition also increases the susceptibility of OVCAR3 cells to TRAIL-induced apoptosis. Finally, over-expression of cFLIP blocks reovirus-induced sensitization of OVCAR3 cells to TRAIL-induced apoptosis. The combination of reovirus and TRAIL thus represents a promising new therapeutic approach for the treatment of ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Down-Regulation
  • Female
  • Humans
  • Mammalian orthoreovirus 3 / pathogenicity*
  • Mitochondria / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Ovarian Neoplasms / virology
  • Recombinant Proteins / pharmacology
  • Reoviridae Infections / metabolism*
  • Reoviridae Infections / pathology*
  • Signal Transduction / drug effects
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • CASP8 protein, human
  • Caspase 8