Expression of an IGF-I receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells

Int J Cancer. 2002 Sep 1;101(1):11-6. doi: 10.1002/ijc.10537.


IGF-IR plays an essential role in the establishment and maintenance of the transformed phenotype of ES cells and interference with the IGF-IR pathways causes reversal of the malignant potential of this neoplasm. In this report, we stably transfected a dominant negative IGF-IR expression plasmid in an ES cell line to determine the effectiveness of this strategy against the in vitro and in vivo growth of ES cells. DXR sensitivity of TC-71 cells expressing dominant negative mutants of IGF-IR was also examined. The mutated IGF-IR that we used carries a mutation in the ATP-binding domain of the intracellular beta subunit, while the extracellular, ligand-binding alpha subunit remains unchanged. Cells carrying the dominant mutant IGF-IR had a marked decrease in proliferation, a significant increase in anoikis-induced apoptosis and a severely reduced ability to form colonies in soft agar. In vivo, when cells carrying dominant negative IGF-IR were injected into nude mice, the tumor formation and metastatic abilities of ES cells were reduced and survival increased. Furthermore, transfected clones showed significantly higher sensitivity to DXR, a major drug in the treatment of ES. These results indicate that the IGF/IGF-IR stimulation of ES cells may be inhibited by expression of mutated IGF-IR on their surfaces and that this strategy may be considered a possible alternative to impair this important target of ES cells, whose therapeutic potential was further confirmed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Doxorubicin / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Mice
  • Mice, Nude
  • Mutation*
  • Neoplasm Transplantation
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism*
  • Sarcoma, Ewing / drug therapy*
  • Sarcoma, Ewing / genetics
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / pathology*
  • Survival Rate
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured


  • Doxorubicin
  • Receptor, IGF Type 1