Malignant ascites protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway in human ovarian carcinoma cells

Int J Cancer. 2007 Sep 15;121(6):1227-37. doi: 10.1002/ijc.22840.


Ascites are commonly found in ovarian cancer patients with advanced disease and are rich in cellular components and growth-promoting factors. The purpose of this study was to assess the effect of malignant ascites on TRAIL-induced apoptosis. We demonstrate that malignant ascites obtained from women with advanced ovarian cancer protect tumor cells from TRAIL- and FasL-induced apoptosis but not against cisplatin-induced apoptosis. This antiapoptotic effect was consistently found among different malignant ascites while nonmalignant peritoneal fluids or conditioned medium from TRAIL-resistant cells failed to protect tumor cells against TRAIL killing. Malignant ascites strongly inhibits TRAIL-induced caspase-3 activation and PARP cleavage. Furthermore, ascites activate PI3K and its downstream target Akt and increases c-FLIP(S) protein levels without affecting ERK phosphorylation status. The antiapoptotic effect of malignant ascites is abrogated by the inhibition of PI3K with LY294002, by a specific inhibitor of Akt and by Akt siRNA. We further show that the pro-survival effect of ascites can be suppressed by down-regulation of c-FLIP(S). Our data indicate that malignant effusions protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway. These findings demonstrate that the tumor microenvironment may contribute to the resistance of ovarian cancer cells to death receptor-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Ascitic Fluid / metabolism*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / drug effects
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Cisplatin / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Morpholines / pharmacology
  • Ovarian Neoplasms / metabolism*
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / drug effects
  • TNF-Related Apoptosis-Inducing Ligand / metabolism


  • Antineoplastic Agents
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Cisplatin