Inhibition of N-linked glycosylation down-regulates insulin-like growth factor-1 receptor at the cell surface and kills Ewing's sarcoma cells: therapeutic implications.
The insulin-like growth factor-1 receptor (IGF-1R) has been shown to be of critical importance for tumor development and tumor cell survival of various types of malignancies. We have previously demonstrated that an adequate N-linked glycosylation of IGF-1R is required for its translocation to the cell surface in melanoma cells. This raises the possibility of using glycosylation inhibitors as therapeutic agents against IGF-1R-dependent malignancies. In this study we show that inhibition of N-linked glycosylation using tunicamycin or the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin resulted in down-regulation of IGF-1R at the cell surface in Ewing's sarcoma cell lines (RD-ES and ES-1 cells). The down-regulation of plasma membrane-bound IGF-1R was correlated with a drastic decrease in IGF-1R autophosphorylation, suggesting biochemical inactivation of the receptor. Whereas RD-ES and ES-1 cells responded differently with regard to DNA synthesis, the decrease in IGF-1R expression was accompanied by a rapid and substantial decrease in survival of both cell lines. Our data suggest that relatively untoxic HMG-CoA reductase inhibitors (e.g. lovastatin) could have therapeutic significance in IGF-1R-dependent neoplasms like Ewing's sarcoma.
Girnita
L
L
Department of Oncology and Pathology, Cellular and Molecular Tumor Pathology, Karolinska Hospital, Stockholm, Sweden.
Wang
M
M
Xie
Y
Y
Nilsson
G
G
Dricu
A
A
Wejde
J
J
Larsson
O
O
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006031:Glycosylation; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014415:Tunicamycin / Q000494:pharmacology
D000970:Antineoplastic Agents; D014415:Tunicamycin; D008148:Lovastatin; D017526:Receptor, IGF Type 1