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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 01; 101(1):11-6.IJ

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 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.

Authors+Show Affiliations

Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna, Italy. katia.scotlandi@ior.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12209582

Citation

Scotlandi, Katia, et al. "Expression of an IGF-I Receptor Dominant Negative Mutant Induces Apoptosis, Inhibits Tumorigenesis and Enhances Chemosensitivity in Ewing's Sarcoma Cells." International Journal of Cancer, vol. 101, no. 1, 2002, pp. 11-6.
Scotlandi K, Avnet S, Benini S, et al. 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;101(1):11-6.
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. (2002). Expression of an IGF-I receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells. International Journal of Cancer, 101(1), 11-6.
Scotlandi K, et al. 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. PubMed PMID: 12209582.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of an IGF-I receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells. AU - Scotlandi,Katia, AU - Avnet,Sofia, AU - Benini,Stefania, AU - Manara,Maria Cristina, AU - Serra,Massimo, AU - Cerisano,Vanessa, AU - Perdichizzi,Stefania, AU - Lollini,Pier-Luigi, AU - De Giovanni,Carla, AU - Landuzzi,Lorena, AU - Picci,Piero, PY - 2002/9/5/pubmed PY - 2002/9/24/medline PY - 2002/9/5/entrez SP - 11 EP - 6 JF - International journal of cancer JO - Int J Cancer VL - 101 IS - 1 N2 - 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. SN - 0020-7136 UR - https://www.unboundmedicine.com/medline/citation/12209582/Expression_of_an_IGF_I_receptor_dominant_negative_mutant_induces_apoptosis_inhibits_tumorigenesis_and_enhances_chemosensitivity_in_Ewing's_sarcoma_cells_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0020-7136&date=2002&volume=101&issue=1&spage=11 DB - PRIME DP - Unbound Medicine ER -