title: Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling.
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.
authors.affiliation: 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.
authors.forename: Demirkan B
authors.initials: DB
authors.lastname: Gürsel
authors.forename: Matei A
authors.initials: MA
authors.lastname: Banu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Berry
authors.forename: Roberta
authors.initials: R
authors.lastname: Marongiu
authors.forename: Jan-Karl
authors.initials: JK
authors.lastname: Burkhardt
authors.forename: Keith
authors.initials: K
authors.lastname: Kobylarz
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: John A
authors.initials: JA
authors.lastname: Boockvar
mesh_terms: D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D001932:Brain Neoplasms / Q000503:physiopathology*; D063646:Carcinogenesis; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D005909:Glioblastoma / Q000503:physiopathology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D014411:Neoplastic Stem Cells / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; C505407:CASP3 protein, human; D053148:Caspase 3