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.