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Dual targeting of IGF-1R and PDGFR inhibits proliferation in high-grade gliomas cells and induces radiosensitivity in JNK-1 expressing cells

  • Lab. Investigation-Human/Animal Issue
  • Published:
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Abstract

Increased expression and activation of receptor tyrosine kinases frequently occur in human brain tumors, mediating a variety of growth-promoting pathways and leading to radioresistance; however, little is known about their motogenic potency relative to one another. In this study, we found co-expression of Insulin like growth factor-1 receptor (IGF-1R) and platelet derived growth factor receptor (PDGFR) in two high-grade gliomas (HGG) cell lines 18 and 38. Dual targeting of IGF-1R and PDGFR increased cell death in both 18 and 38 cell lines in comparison to inhibition of either receptor alone. In addition, co-inhibition of IGF-1R and PDGFR increased radiosensitivity in 18 cells but failed to intensify the effect of radiation in 38 cells. In HGG cells, radiation-induced cell death has been connected to the activation of c-Jun-NH2-terminal kinase-1 (JNK1). We found that JNK1 was weakly expressed in 38 cells while it had an elevated expression in 18 cells. Exposure to ionizing radiation induced JNK1 activation only in 18 cells without affecting the protein activity in 38 cells. These results suggest that in 18 cell line radiation-activated JNK1 may provide an anti-proliferative signaling, parallel to receptors co-targeting. To test this hypothesis, HGG cells were treated with dominant negative JNK1 (dnJNK1) and the response to radiation was assayed in presence or absence of receptors co-inhibition. Indeed dnJNK protected 18 cells against γ-irradiation-induced cell death. dnJNK treatment did not influence radiation response of the 38 cell line, which expressed low levels of JNK1. In conclusion we found that IGF-1R and PDGFR co-inhibition caused an increased cell death in two HGG cell line and induced the radiosensitization of the JNK1 expressing cell line.

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Abbreviations

IGF-1R:

Insulin like growth factor-1 receptor

PDGFR:

Platelet derived growth factor receptor

RTKs:

Receptor tyrosine kinases

HGG:

High-grade gliomas

JNK1:

c-Jun-NH2-terminal kinase-1

dnJNK:

Dominant negative JNK1

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Acknowledgments

Grant support: European Commission grant QLGA-CT-2000-60005, Swedish Society of Medicine and The National Board of Health and Welfare Stockholm.

The authors gratefully acknowledge Dr Lynn Heasly (University of Colorado, Denver) for providing dnJNK1.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Cancer Center Karolinska and Radiumhemmet Karolinska Institute/University Hospital, R8:00, Stockholm, 171 76, Sweden

    Mia Carapancea, Daria Cosaceanu, Raluca Budiu, Anna Kwiecinska, Oana Alexandru, Magnus L. Bäcklund, Rolf Lewensohn & Anica Dricu

  2. Department of Neurosurgery, Bagdasar-Arseni Hospital, Bucharest, Romania

    Ligia Tataranu & Vasile Ciubotaru

  3. University of Medicine and Pharmacy, Craiova, Romania

    Monica Banita & Catalina Pisoschi

Authors
  1. Mia Carapancea
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  2. Daria Cosaceanu
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Correspondence to Anica Dricu.

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Carapancea, M., Cosaceanu, D., Budiu, R. et al. Dual targeting of IGF-1R and PDGFR inhibits proliferation in high-grade gliomas cells and induces radiosensitivity in JNK-1 expressing cells. J Neurooncol 85, 245–254 (2007). https://doi.org/10.1007/s11060-007-9417-0

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  • DOI: https://doi.org/10.1007/s11060-007-9417-0

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