gsk3β regulates differentiation and growth arrest in glioblastomagsk3β调节分化和生长在胶质母细胞瘤被捕.pdfVIP

GSK3b Regulates Differentiation and Growth Arrest in Glioblastoma 1 1 1 1 2 Serdar Korur , Roland M. Huber , Balasubramanian Sivasankaran , Michael Petrich , Pier Morin Jr , 2 1 1 Brian A. Hemmings , Adrian Merlo *, Maria Maddalena Lino 1 Laboratory of Molecular Neuro-Oncology, University Hospital Basel, Basel, Switzerland, 2 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Abstract Cancers are driven by a population of cells with the stem cell properties of self-renewal and unlimited growth. As a subpopulation within the tumor mass, these cells are believed to constitute a tumor cell reservoir. Pathways controlling the renewal of normal stem cells are deregulated in cancer. The polycomb group gene Bmi1, which is required for neural stem cell self-renewal and also controls anti-oxidant defense in neurons, is upregulated in several cancers, including medulloblastoma. We have found that Bmi1 is consistently and highly expressed in GBM. Downregulation of Bmi1 by shRNAs induced a differentiation phenotype and reduced expression of the stem cell markers Sox2 and Nestin. Interestingly, expression of glycogen synthase kinase 3 beta (GSK3b), which was found to be consistently expressed in primary GBM, also declined. This suggests a functional link between Bmi1 and GSK3b. Interference with GSK3b activity by siRNA, the specific inhibitor SB216763, or lithium chloride (LiCl) induced tumor cell differentiation. In addition, tumor cell apoptosis was enhanced, the formation of neurospheres was impaired, and clonogenicity reduced in a dose-dependent manner. GBM cel