TY - JOUR
T1 - Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R
AU - Kalebic, Thea
AU - Blakesley, Vicky
AU - Slade, Crystal
AU - Plasschaert, Sabine
AU - Leroith, Derek
AU - Lee Helman, J.
PY - 1998/4/13
Y1 - 1998/4/13
N2 - Previous results have shown that the insulin-like growth factor type I receptor (IGF-I-R) plays a critical role in the control of rhebdomyosarcoma (RMS) growth. The purpose of this study was to investigate whether a mutated IGF-I-R, when expressed in RMS cells, may interfere with the function of the endogenous wild-type IGF-I-R. We also examined whether the expression of a mutated IGF-1-R may induce phenotypic changes in RMS cells. We used here the mutated IGF-I-R with a lysine to arginine residue 1003 substitution, called IGF-I-KR, which carries a mutation in the AmP-binding domain of the intracellular β subunit, while the extracellular, ligand binding a subunit remains unchanged. We observed that the expression of this mutated IGF-I-KR markedly decreased the response of RMS cells to stimulation with IGF-I. While stimulation with IGF-I increases the autophosphorylation of IGF-I-R in the parent cells, stimulation with IGF-I failed to produce a comparable increase in autophosphorylation in the cells expressing the mutated IGF-I-KR. We also observed a decreased plating efficiency of cells expressing the mutated IGF- I-KR. Consistently, a decrease of RMS growth in viva was observed in an animal model. Our data suggest that the IGF/IGF-I-R signaling pathway may be inhibited by expressing a mutated IGF-1-KR and that such a mutant gene could be utilized in developing novel therapeutic strategies to suppress RMS growth.
AB - Previous results have shown that the insulin-like growth factor type I receptor (IGF-I-R) plays a critical role in the control of rhebdomyosarcoma (RMS) growth. The purpose of this study was to investigate whether a mutated IGF-I-R, when expressed in RMS cells, may interfere with the function of the endogenous wild-type IGF-I-R. We also examined whether the expression of a mutated IGF-1-R may induce phenotypic changes in RMS cells. We used here the mutated IGF-I-R with a lysine to arginine residue 1003 substitution, called IGF-I-KR, which carries a mutation in the AmP-binding domain of the intracellular β subunit, while the extracellular, ligand binding a subunit remains unchanged. We observed that the expression of this mutated IGF-I-KR markedly decreased the response of RMS cells to stimulation with IGF-I. While stimulation with IGF-I increases the autophosphorylation of IGF-I-R in the parent cells, stimulation with IGF-I failed to produce a comparable increase in autophosphorylation in the cells expressing the mutated IGF-I-KR. We also observed a decreased plating efficiency of cells expressing the mutated IGF- I-KR. Consistently, a decrease of RMS growth in viva was observed in an animal model. Our data suggest that the IGF/IGF-I-R signaling pathway may be inhibited by expressing a mutated IGF-1-KR and that such a mutant gene could be utilized in developing novel therapeutic strategies to suppress RMS growth.
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U2 - 10.1002/(SICI)1097-0215(19980413)76:2<223::AID-IJC9>3.0.CO;2-Z
DO - 10.1002/(SICI)1097-0215(19980413)76:2<223::AID-IJC9>3.0.CO;2-Z
M3 - Article
C2 - 9537584
AN - SCOPUS:0032513524
SN - 0020-7136
VL - 76
SP - 223
EP - 227
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 2
ER -