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Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling

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Abstract

Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.

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Acknowledgments

The authors would like to thank Maria Irina Chiriac for excellent technical assistance in preparing the figures of this manuscript.

Disclosure

The authors declare that they have no conflict of interest. The authors report no financial or material support concerning the materials or methods used in this study or the findings specified in this paper.

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Authors and Affiliations

  1. Laboratory for Translational Brain Tumor and Stem Cell Research, Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, 525 East 68th Street, Box 99, New York, NY, 10021, USA

    Demirkan B. Gürsel, Matei A. Banu, Nicholas Berry, Jan-Karl Burkhardt & John A. Boockvar

  2. Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, New York, NY, 10021, USA

    Roberta Marongiu & Michael G. Kaplitt

  3. Department of Genetic Medicine, Howard Hughes Medical Institute, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY, 10021, USA

    Keith Kobylarz & Shahin Rafii

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  1. Demirkan B. Gürsel
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  2. Matei A. Banu
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Correspondence to John A. Boockvar.

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Gürsel, D.B., Banu, M.A., Berry, N. et al. Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling. J Neurooncol 121, 19–29 (2015). https://doi.org/10.1007/s11060-014-1602-3

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