The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38(MAPK) activity

Oncogene. 2008 Feb 7;27(7):985-96. doi: 10.1038/sj.onc.1210705. Epub 2007 Aug 13.


The Ewing's sarcoma family of tumours (ESFT) are small round cell tumours characterized by the non-random EWS-ETS gene rearrangements. We have previously demonstrated that ESFT are highly sensitive to fenretinide-induced death, effected in part through a reactive oxygen species (ROS)-dependent pathway. Here, we demonstrate for the first time that the sensitivity of ESFT cells to fenretinide-induced cell death is decreased following downregulation of the oncogenic fusion protein EWS-Fli1; siRNA targeting EWS-Fli1 attenuated fenretinide-induced cell death in cell lines expressing EWS-Fli1, but not EWS-ERG. This decrease in cell death was independent of the level of ROS produced following exposure to fenretinide, but was effected through EWS-Fli1-dependent modulation of p38(MAPK) activity. Furthermore, inhibition of p38(MAPK) activity and knockdown of EWS-Fli1 reduced fenretinide-induced mitochondrial permeabilization, cytochrome c release, caspase and PARP cleavage, consistent with the hypothesis that p38(MAPK) is critical for activation of the death cascade by fenretinide in ESFT cells. These data demonstrate that expression of EWS-Fli1 enhances fenretinide-induced cell death in ESFT and that this is effected at least in part through modulation of p38(MAPK) activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspases / metabolism
  • Cell Proliferation / drug effects
  • Cytochromes c / metabolism
  • Down-Regulation
  • Electroporation
  • Fenretinide / pharmacology*
  • Flow Cytometry
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Membrane Potentials / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Protein c-fli-1 / antagonists & inhibitors
  • Proto-Oncogene Protein c-fli-1 / genetics
  • Proto-Oncogene Protein c-fli-1 / metabolism*
  • RNA, Small Interfering / pharmacology
  • RNA-Binding Protein EWS
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcoma, Ewing / drug therapy*
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / pathology
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antineoplastic Agents
  • EWS-ERG fusion protein, human
  • EWS-FLI fusion protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA, Small Interfering
  • RNA-Binding Protein EWS
  • Reactive Oxygen Species
  • Transcription Factors
  • Fenretinide
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • p38 Mitogen-Activated Protein Kinases
  • Caspases