Expression of an IGF-I receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells
✍ Scribed by Katia Scotlandi; Sofia Avnet; Stefania Benini; Maria Cristina Manara; Massimo Serra; Vanessa Cerisano; Stefania Perdichizzi; Pier-Luigi Lollini; Carla De Giovanni; Lorena Landuzzi; Piero Picci
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- French
- Weight
- 202 KB
- Volume
- 101
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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.