Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3.
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-3alpha or GSK-3beta 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.
Nowicki
Michal O
MO
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.
Dmitrieva
Nina
N
Stein
Andrew M
AM
Cutter
Jennifer L
JL
Godlewski
Jakub
J
Saeki
Yoshinaga
Y
Nita
Masayuki
M
Berens
Michael E
ME
Sander
Leonard M
LM
Newton
Herbert B
HB
Chiocca
E Antonio
EA
Lawler
Sean
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects; D009924:Organ Culture Techniques
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride