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Tie2-mediated multidrug resistance in malignant gliomas is associated with upregulation of ABC transporters

Oncogene volume 28, pages 2358–2363 (2009)Cite this article

Abstract

Resistance and relapse are still primary causes that result in poor effectiveness of chemotherapy in malignant gliomas. Therefore, development of new therapeutic strategies requires the identification of key molecular pathways regulating chemoresistance. We previously found that abnormal high expression of the Tie2 receptor in gliomas was associated with tumor malignancy. Here, we studied the role of Tie2 activation in drug resistance by testing the cytotoxicity of several chemotherapeutic drugs in a panel of human glioma cell lines and brain tumor stem cells and found that Tie2 activation was significantly related to chemoresistance. The essential role of Tie2 in this phenotype was illustrated by silencing Tie2 using specific siRNA, and the subsequent abrogation of the angiopoietin 1 (Ang1)-mediated chemoresistance. Using quantitative real-time PCR and functional drug efflux studies, we observed that Tie2 activation resulted in increased expression of ATP-binding cassette (ABC) transporters. Consistent with these results, downmodulation of ABCG2 or ABCC2 resulted in the inability of Tie2 activation to induce a chemoresistant phenotype. Our results indicate that Tie2 activation may be important in modifying the evolution of gliomas during conventional chemotherapy regimens, and open new avenues for the search of more effective therapies to avoid the inevitable brain tumor recurrence.

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Acknowledgements

We thank Alyson Todd (Department of Scientific Publications, The University of Texas MD Anderson Cancer Center) for editorial assistance. This work was supported by a postdoctoral fellowship from the Department of Education and Science, Spain (to VM), an American Brain Tumor Association postdoctoral fellowship (to DL), Elsa U Pardee Foundation Award (to CGM), and an NIH/Developmental Research Program P50CA127001 (to CGM).

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Authors and Affiliations

  1. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    V Martin, J Xu, S K Pabbisetty, M M Alonso, D Liu, O-H Lee, H Colman, J Fueyo & C Gomez-Manzano

  2. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Gumin & F F Lang

  3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K P Bhat

  4. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Gomez-Manzano

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  1. V Martin
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  2. J Xu
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  3. S K Pabbisetty
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  4. M M Alonso
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  5. D Liu
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Correspondence to C Gomez-Manzano.

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

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Martin, V., Xu, J., Pabbisetty, S. et al. Tie2-mediated multidrug resistance in malignant gliomas is associated with upregulation of ABC transporters. Oncogene 28, 2358–2363 (2009). https://doi.org/10.1038/onc.2009.103

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