Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R

Thea Kalebic, Vicky Blakesley, Crystal Slade, Sabine Plasschaert, Derek Leroith, J. Lee Helman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-227
Number of pages5
JournalInternational Journal of Cancer
Volume76
Issue number2
DOIs
StatePublished - Apr 13 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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