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Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

We previously showed that inhibition of the platelet-derived growth factor receptor (PDGFR) blocks the survival and migration of medulloblastoma cells. Identification of in vitro PDGFR-targeting pharmacologic agents that are suitable for preclinical testing in medulloblastoma models in vivo will be critical for efficiently translating these agents to clinical investigation in children with medulloblastoma. In this study, we investigated whether the multi-tyrosine kinase inhibitor sunitinib, effectively inhibits PDGFR signaling required for medulloblastoma cell migration. Daoy and D556 human medulloblastoma cells pre-treated for 1 h with 0.2 μM sunitinib demonstrated induction of PTEN expression and significant inhibition of PDGFR signaling activity and transactivation of EGFR, in a RAS-independent manner, in response to PDGF-BB stimulation. Sunitinib pre-treatment markedly reduced medulloblastoma cell migration in response to both PDGF-BB and 10% serum at 4 and 24 h after treatment. Pre-treatment with sunitinib for 1 h also resulted in detachment and decreased viability of D556, but not Daoy, cells and only after 48 h following treatment. However, sunitinib did not induce apoptosis in either cell line at any time point, indicating that the anti-migratory effects of sunitinib were not due to impeding cell survival. Sunitinib similarly inhibited PDGFR signaling and migration of primary murine Smo/Smo medulloblastoma cells, suggesting that the Smo/Smo mouse is an appropriate model for preclinical testing of sunitinib. These results indicate that sunitinib may be an important pharmacologic agent for the treatment of invasive medulloblastoma, particularly given evidence of its ability to cross the blood–brain barrier to target tumor cells, and thus warrants further in vivo testing for confirmation of efficacy.

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References

  1. Giangaspero F, Bigner SH, Kleihues P et al (2000) Medulloblastoma. In: Kleihues P, Cavanee WK (eds) World health organization classification of tumours: pathology and genetics of tumours of the nervous system. International Agency for Research on Cancer, Lyon

    Google Scholar 

  2. McLean TW (2003) Medulloblastomas and central nervous system primitive neuroectodermal tumours. Curr Treat Options Oncol 4:499–508

    Article  PubMed  Google Scholar 

  3. Packer RJ, Rood BR, Macdonald TJ (2003) Medulloblastoma: present concepts of stratification into risk groups. Pediatr Neurosurg 39:60–67

    Article  PubMed  Google Scholar 

  4. Abouantoun TJ, MacDonald TJ (2009) Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of pf epidermal growth factor receptor. Mol Cancer Ther 8:1137–1147

    Article  CAS  Google Scholar 

  5. Koutras AK, Krikelis D, Alexandrou N et al (2007) Brain metastasis in renal cell cancer responding to sunitinib. Anticancer Res 27:4255–4257

    CAS  PubMed  Google Scholar 

  6. Mendel DB, Laird AD, Xin X et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337

    CAS  PubMed  Google Scholar 

  7. Motzer RJ, Hutson TE, Tomczak P (2007) SUTENT versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  CAS  PubMed  Google Scholar 

  8. Croyle M, Akeno N, Knauf JA et al (2008) RET/PTC-induced cell growth is mediated in part by epidermal growth factor receptor (EGFR) activation: evidence for molecular and functional interactions between RET and EGFR. Cancer Res 68:4183–4191

    Article  CAS  PubMed  Google Scholar 

  9. Decker SJ, Harris P (1989) Effects of platelet-derived growth factor on phosphorylation of the epidermal growth factor receptor in human skin fibroblast. J Biol Chem 264:9204–9209

    CAS  PubMed  Google Scholar 

  10. Liu P, Ying Y, Ko YG et al (1996) Localization of platelet-derived growth factor-stimulated phosphorylation cascade to caveolae. J Biol Chem 271:10299–10303

    Article  CAS  PubMed  Google Scholar 

  11. Li J, Kim YN, Bertics PJ (2000) Platelet-derived growth factor stimulated migration of murine fibroblasts is associated with epidermal growth factor receptor expression and tyrosine phosphorylation. J Biol Chem 275:2951–2958

    Article  CAS  PubMed  Google Scholar 

  12. He H, Levitzki A, Zhu HJ et al (2001) Platelet-derived growth factor requires epidermal growth factor receptor to activate p21-activated kinase family kinases. J Biol Chem 276:26741–26744

    Article  CAS  PubMed  Google Scholar 

  13. Saito Y, Haendeler J, Hojo Y et al (2001) Receptor heterodimerization: essential mechanism for platelet-derived growth factor-induced epidermal growth factor receptor transactivation. Mol Cell Biol 21:6387–6394

    Article  CAS  PubMed  Google Scholar 

  14. Osusky KL, Hallahan DE, Fu A et al (2004) The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels. Angiogenesis 7:225–233

    Article  CAS  PubMed  Google Scholar 

  15. De Bouard S, Herlin P, Christensen JG et al (2007) Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol 9:412–423

    Article  PubMed  Google Scholar 

  16. Hatton BA, Villavicencio EH, Tsuchiya KD, Pritchard JI et al (2008) The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res 15:1768–1776

    Article  Google Scholar 

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Acknowledgments

Sunitinib was provided by Pfizer Pharma. Supported by NIH R01 grant CA111835 (T.J.M.).

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Authors and Affiliations

  1. Children’s Research Institute, Center for Cancer and Immunology Research, Children’s National Medical Center and The George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA

    Thamara J. Abouantoun

  2. Emory University School of Medicine, Atlanta, GA, USA

    Robert C. Castellino

  3. Children’s Healthcare of Atlanta, Aflac Cancer Center and Blood Disorders Service, Emory Children’s Center, Emory University, 2015 Uppergate Drive NE, Suite 442, Atlanta, GA, 30322, USA

    Tobey J. MacDonald

Authors
  1. Thamara J. Abouantoun
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  2. Robert C. Castellino
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  3. Tobey J. MacDonald
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Correspondence to Tobey J. MacDonald.

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Abouantoun, T.J., Castellino, R.C. & MacDonald, T.J. Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells. J Neurooncol 101, 215–226 (2011). https://doi.org/10.1007/s11060-010-0259-9

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  • DOI: https://doi.org/10.1007/s11060-010-0259-9

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