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  • The Regulation of Proliferation and Programmed Cell Death in Patient GBM Stem-Like Cells by EGFR/GSK3b/PP2A Signaling

    Final Number:

    Demirkan B. Gursel PhD; Nicholas Berry; Keith Kobylarz; Cody D Schlaff, BS; Jan-karl Burkhardt MD; Matei A Banu MD; Shahin Rafii MD; John A. Boockvar MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2012 Annual Meeting

    Introduction: High grade gliomas are incurable brain tumors with dismal prognosis. A small subpopulation of cells with stem-like characteristics located in a tightly controlled microenvironment, the perivascular niche, has been postulated to initiate and maintain the tumor’s neoplasticity and contribute to its therapeutic resistance. The discovery of novel molecular targets contributing to the pathology of aggressive gliomas is urgently required. The study presented here aims to define the regulation of glycogen synthase kinase 3 beta (GSK3beta) activity in GBM biology by using stem-like cells derived from human GBM patients.

    Methods: To evaluate the possible deregulation of GSK3b in glioblastoma, tissues from 68 GBM patients, 20 normal brains either neocortex or hippocampus and GBM stem-like cells were analyzed for GSK3b and EGFR/pI3kinase-mediated signaling mechanisms.

    Results: More than 60% of GBM patients downregulated GSK3b compared to normal tissue, which suggests a possible association of GSK3b deregulation in GBM pathology. GBM stem-like cells responded to exogenous EGF by phosphorylating EGFR, AKT and GSK3b. Blocking the phosphorylation of GSK3b at Serine 9 attenuated cell proliferation while stimulating apoptosis through cleaved Caspase-3. Overexpression of GSK3b resulted in inhibition of cell proliferation, colony formation, and apoptosis, which strongly indicates an active role of GSK3b in tumorigenesis. To clarify the mechanism through which GSK3b may be regulated by cross-talk, GSK3b activity in GBM stem-like cells was knocked down and analyzed for the interaction of PP2A with GSK3b. Silencing PP2A on B subunit and/or inactivation of PP2A by okadaic acid interrupted GSK3b function, which suggests that PP2A may regulate GSK3b apototic activity.

    Conclusions: Increasing evidence suggests aberrant signaling of EGFR, GSK3b and PP2A contributes to glial tumorigenesis. Therapeutic approaches targeting GSK3b in glioblastoma stem cells (GSCs) may assist in the future treatment of GBM.

    Patient Care: The signaling pathways explored in this study could serve as targets for future anti-cancer therapies.

    Learning Objectives: By the end of this presentation, participants will better understand the aberrant molecular signaling in brain tumors, how this signaling contributes to tumorigenicity, and how the identification of these signaling pathways may provide molecular targets for future therapeutics.


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