GSK3beta regulates differentiation and growth arrest in glioblastoma.
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 (GSK3beta), which was found to be consistently expressed in primary GBM, also declined. This suggests a functional link between Bmi1 and GSK3beta. Interference with GSK3beta 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 cell lines consist mainly of CD133-negative (CD133-) cells. Interestingly, ex vivo cells from primary tumor biopsies allowed the identification of a CD133- subpopulation of cells that express stem cell markers and are depleted by inactivation of GSK3beta. Drugs that inhibit GSK3, including the psychiatric drug LiCl, may deplete the GBM stem cell reservoir independently of CD133 status.
Korur
Serdar
S
Laboratory of Molecular Neuro-Oncology, University Hospital Basel, Basel, Switzerland.
Huber
Roland M
RM
Sivasankaran
Balasubramanian
B
Petrich
Michael
M
Morin
Pier
P
Hemmings
Brian A
BA
Merlo
Adrian
A
Lino
Maria Maddalena
MM
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides; D010641:Phenotype; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism
D000071916:AC133 Antigen; D015703:Antigens, CD; C069077:BMI1 protein, human; D006023:Glycoproteins; D009687:Nuclear Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3