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Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo

Oncogene volume 27, pages 2910–2922 (2008)Cite this article

Abstract

Mammalian target of rapamycin (mTOR) has been shown to play an important function in cell proliferation, metabolism and tumorigenesis, and proteins that regulate signaling through mTOR are frequently altered in human cancers. In this study we investigated the phosphorylation status of key proteins in the PI3K/AKT/mTOR pathway and the effects of the mTOR inhibitors rapamycin and CCI-779 on neuroblastoma tumorigenesis. Significant expression of activated AKT and mTOR were detected in all primary neuroblastoma tissue samples investigated, but not in non-malignant adrenal medullas. mTOR inhibitors showed antiproliferative effects on neuroblastoma cells in vitro. Neuroblastoma cell lines expressing high levels of MYCN were significantly more sensitive to mTOR inhibitors compared to cell lines expressing low MYCN levels. Established neuroblastoma tumors treated with mTOR inhibitors in vivo showed increased apoptosis, decreased proliferation and inhibition of angiogenesis. Importantly, mTOR inhibitors induced downregulation of vascular endothelial growth factor A (VEGF-A) secretion, cyclin D1 and MYCN protein expression in vitro and in vivo. Our data suggest that mTOR inhibitors have therapeutic efficacy on aggressive MYCN amplified neuroblastomas.

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Acknowledgements

We thank M Schwab (German Cancer Research Centre, DKFZ, Heidelberg, Germany) for providing us with the Tet21N cell line. This work was supported by grants from the Swedish Childhood Cancer Foundation, The Swedish Cancer Foundation, The Swedish Research Council and Märta and Gunnar V Philipson Foundation.

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Author notes

  1. J I Johnsen and L Segerström: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Woman and Child Health, Karolinska Institutet, Childhood Cancer Research Unit, Stockholm, Sweden

    J I Johnsen, L Segerström, L Elfman, S Eksborg, B Sveinbjörnsson & P Kogner

  2. Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden

    A Orrego

  3. Department of Microbiology, Tumor and Cellbiology, Karolinska Institutet, Stockholm, Sweden

    M Henriksson

  4. Division of Clinical Chemistry, Faculty of Health Sciences, Linköping University, Sweden

    B Kågedal

  5. Department of Cell Biology and Histology, University of Tromsö, Tromsö, Norway

    B Sveinbjörnsson

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  1. J I Johnsen
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Correspondence to L Segerström.

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Johnsen, J., Segerström, L., Orrego, A. et al. Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene 27, 2910–2922 (2008). https://doi.org/10.1038/sj.onc.1210938

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