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

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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-3β constitutive phosphorylation and was independent from T-antigen-mediated cellular events (Supplementary Materials). BsB8 cells were partially rescued from NVP-AEW541 by GSK3β inhibitor, lithium chloride and were sensitized by GSK3β 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 GSK3β dephosphorylation (activation). Our results indicate that hypersensitivity of medulloblastoma cells in anchorage-independence is linked to GSK-3β activity and suggest that pharmacological intervention against IGF-IR with simultaneous activation of GSK3β could be highly effective against medulloblastomas, which have intrinsic ability of disseminating the CNS via cerebrospinal fluid.

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Acknowledgements

We gratefully acknowledge Dr Olaf Mundigl (Roche Diagnostics, Penzberg, Germany) for providing an antibody against phosphorylated IGF-IR, and Dr Martyn White for his editorial help. This work was supported by grants from NIH: RO1CA095518-01 (KR) and PO1 NS36466-06 (KK, KR).

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Authors and Affiliations

  1. Department of Neuroscience, Center for Neurovirology, Temple University, Philadelphia, PA, USA

    K Urbanska, J Trojanek, L Del Valle, M B Eldeen, K Khalili & K Reiss

  2. Department of Cell Biology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland

    K Urbanska

  3. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland

    F Hofmann & C Garcia-Echeverria

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  1. K Urbanska
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  2. J Trojanek
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  3. L Del Valle
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Correspondence to K Reiss.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Urbanska, K., Trojanek, J., Del Valle, L. et al. Inhibition of IGF-I receptor in anchorage-independence attenuates GSK-3β constitutive phosphorylation and compromises growth and survival of medulloblastoma cell lines. Oncogene 26, 2308–2317 (2007). https://doi.org/10.1038/sj.onc.1210018

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