Inhibition of IGF-I receptor in anchorage-independence attenuates GSK-3beta constitutive phosphorylation and compromises growth and survival of medulloblastoma cell lines.

Abstract

We have previously reported that insulin-like growth factor-I (IGF-I) supports growth and survival of mouse and human medulloblastoma cell lines, and that IGF-I receptor (IGF-IR) is constitutively phosphorylated in human medulloblastoma clinical samples. Here, we demonstrate that a specific inhibitor of insulin-like growth factor-I receptor (IGF-IR), NVP-AEW541, attenuated growth and survival of mouse (BsB8) and human (D384, Daoy) medulloblastoma cell lines. Cell cycle analysis demonstrated that G1 arrest and apoptosis contributed to the action of NVP-AEW54. Interestingly, very aggressive BsB8 cells, which derive from cerebellar tumors of transgenic mice expressing viral oncoprotein (large T-antigen from human polyomavirus JC) became much more sensitive to NVP-AEW541 when exposed to anchorage-independent culture conditions. This high sensitivity to NVP-AEW54 in suspension was accompanied by the loss of GSK-3beta constitutive phosphorylation and was independent from T-antigen-mediated cellular events (Supplementary Materials). BsB8 cells were partially rescued from NVP-AEW541 by GSK3beta inhibitor, lithium chloride and were sensitized by GSK3beta activator, sodium nitroprusside (SNP). Importantly, human medulloblastoma cells, D384, which demonstrated partial resistance to NVP-AEW541 in suspension cultures, become much more sensitive following SNP-mediated GSK3beta dephosphorylation (activation). Our results indicate that hypersensitivity of medulloblastoma cells in anchorage-independence is linked to GSK-3beta activity and suggest that pharmacological intervention against IGF-IR with simultaneous activation of GSK3beta could be highly effective against medulloblastomas, which have intrinsic ability of disseminating the CNS via cerebrospinal fluid.

• Authors: K Urbanska, J Trojanek, L Del Valle, M B Eldeen, F Hofmann, C Garcia-Echeverria, K Khalili, K Reiss
• Journal: Oncogene (Oncogene) Vol. 26 Issue 16 Pg. 2308-17 (Apr 05 2007) ISSN: 0950-9232 [Print] England
• PMID: 17016438 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptor, IGF Type 1
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cell Division
• Cell Line, Tumor
• Cell Survival
• Cerebellar Neoplasms (pathology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Male
• Medulloblastoma (pathology)
• Mice
• Mice, Transgenic
• Phosphorylation
• Receptor, IGF Type 1 (antagonists & inhibitors)