1. Expression of an IGF-I receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells
- Author
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Scotlandi K., Avnet S., Benini S., Manara M. C., Serra M., Cerisano V., Perdichizzi S., Lollini P. -L., De Giovanni C., Landuzzi L., Picci P., Scotlandi K., Avnet S., Benini S., Manara M.C., Serra M., Cerisano V., Perdichizzi S., Lollini P.-L., De Giovanni C., Landuzzi L., and Picci P. more...
- Subjects
Time Factors ,Time Factor ,Cell Survival ,Blotting, Western ,Mice, Nude ,Apoptosis ,Sarcoma, Ewing ,Transfection ,Receptor, IGF Type 1 ,Mice ,Tumor Cells, Cultured ,Animals ,Insulin-like growth factor-I ,Chemosensitivity ,Tumorigenesi ,Animal ,Apoptosi ,Ewing's sarcoma ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Doxorubicin ,Dominant negative mutant ,Mutation ,Nude mice ,Cell Division ,Neoplasm Transplantation - Abstract
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 β subunit, while the extracellular, ligand-binding α 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. © 2002 Wiley-Liss, Inc. more...
- Published
- 2002