Lithium inhibits invasion of glioma cells possible involvement of glycogen synthase kinase-3
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Posted on: 10/19/2008
First published on August 20, 2008
This version was published on January 1, 2008
Neuro Oncol 2008 10(5):690-699; DOI:10.1215/15228517-2008-041
Basic and Translational Investigations
Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3
Michal O. Nowicki, Nina Dmitrieva, Andrew M. Stein, Jennifer L. Cutter, Jakub Godlewski, Yoshinaga Saeki, Masayuki Nita, Michael E. Berens, Leonard M. Sander, Herbert B. Newton, E. Antonio Chiocca and Sean Lawler
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, OH (M.O.N., J.L.C., J.G., N.D, E.A.C., S.E.L, Y.S., M.N., H.N.); Michigan Center for Theoretical Physics and Department of Physics, University of Michigan, Ann Arbor, MI (A.M.S., L.M.S.); Translational Genomics Institute, Phoenix, AZ (M.E.B.), USA
Address correspondence to E. Antonio Chiocca or Sean Lawler, Dept. of Neurological Surgery, The Ohio State University Medical Center Wiseman Hall, 400 West 12th Avenue, Columbus, OH 43210 (EA.Chiocca@osumc.edu or Sean.Lawler@osumc.edu).
Therapies targeting glioma cells that diffusely infiltrate normal brain are highly sought after. Our aim was to identify novel approaches to this problem using glioma spheroid migration assays. Lithium, a currently approved drug for the treatment of bipolar illnesses, has not been previously examined in the context of glioma migration. We found that lithium treatment potently blocked glioma cell migration in spheroid, wound-healing, and brain slice assays. The effects observed were dose dependent and reversible, and worked using every glioma cell line tested. In addition, there was little effect on cell viability at lithium concentrations that inhibit migration, showing that this is a specific effect. Lithium treatment was associated with a marked change in cell morphology, with cells retracting the long extensions at their leading edge. Examination of known targets of lithium showed that inositol monophosphatase inhibition had no effect on glioma migration, whereas inhibition of glycogen synthase kinase-3 (GSK-3) did. This suggested that the effects of lithium on glioma cell migration could possibly be mediated through GSK-3. Specific pharmacologic GSK-3 inhibitors and siRNA knockdown of GSK-3 or GSK-3β isoforms both reduced cell motility. These data outline previously unidentified pathways and inhibitors that may be useful for the development of novel anti-invasive therapeutics for the treatment of brain tumors.
Key Words: glioma • GSK-3 • invasion • lithium • motility
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