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PMID: 18715951 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3.

Neuro-oncology ·Vol. 10 ·No. 5 ·2008-10-00 ·Pages 690-9

Nowicki MO, Dmitrieva N, Stein AM, Cutter JL, Godlewski J, Saeki Y, Nita M, Berens ME, Sander LM, Newton HB, Chiocca EA, Lawler S

Abstract

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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Blotting, Western Brain Neoplasms/enzymology,pathology Cell Cycle/drug effects Cell Line, Tumor Cell Movement/drug effects Enzyme Inhibitors/pharmacology Glioma/enzymology,pathology Glycogen Synthase Kinase 3/drug effects,metabolism Humans Lithium Chloride/pharmacology Mice Neoplasm Invasiveness/physiopathology Neurons/drug effects Organ Culture Techniques
Chemicals
Antineoplastic Agents Enzyme Inhibitors Glycogen Synthase Kinase 3 Lithium Chloride
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Nowicki Michal O
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.
Dmitrieva Nina
Stein Andrew M
Cutter Jennifer L
Godlewski Jakub
Saeki Yoshinaga
Nita Masayuki
Berens Michael E
Sander Leonard M
Newton Herbert B
Chiocca E Antonio
Lawler Sean
References (45)
45 references, click to expand
  1. Glycogen synthase kinase-3 acts upstream of ADP-ribosylation factor 6 and Rac1 to regulate epithelial cell migration.
    Exp Cell Res. 2006 May 15;312(9):1514-25 PMID: 16529739
  2. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity.
    Cell. 2005 Jan 14;120(1):137-49 PMID: 15652488
  3. Initiation of DNA synthesis in mammary epithelium and mammary tumors by lithium ions.
    J Cell Physiol. 1980 Apr;103(1):41-6 PMID: 7000799
  4. In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330.
    J Neurochem. 1993 Feb;60(2):652-8 PMID: 8380439
  5. Cost of migration: invasion of malignant gliomas and implications for treatment.
    J Clin Oncol. 2003 Apr 15;21(8):1624-36 PMID: 12697889
  6. Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation.
    J Neurooncol. 2006 Jul;78(3):295-302 PMID: 16636750
  7. Cytoprotection by lithium and valproate varies between cell types and cellular stresses.
    Eur J Pharmacol. 2006 Jun 6;539(1-2):18-26 PMID: 16678157
  8. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling.
    Dev Cell. 2003 Sep;5(3):367-77 PMID: 12967557
  9. A mathematical model of glioblastoma tumor spheroid invasion in a three-dimensional in vitro experiment.
    Biophys J. 2007 Jan 1;92(1):356-65 PMID: 17040992
  10. Inhibition of glycogen synthase kinase 3beta in sensory neurons in culture alters filopodia dynamics and microtubule distribution in growth cones.
    Mol Cell Neurosci. 2003 Aug;23(4):626-37 PMID: 12932442
  11. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
    Nature. 1995 Dec 21-28;378(6559):785-9 PMID: 8524413
  12. AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test.
    Int J Neuropsychopharmacol. 2004 Dec;7(4):387-90 PMID: 15315719
  13. Invasive behaviour of glioblastoma cell lines is associated with altered organisation of the cadherin-catenin adhesion system.
    J Cell Sci. 2002 Aug 15;115(Pt 16):3331-40 PMID: 12140264
  14. Glycogen synthase kinase 3 and h-prune regulate cell migration by modulating focal adhesions.
    Mol Cell Biol. 2006 Feb;26(3):898-911 PMID: 16428445
  15. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3.
    J Biol Chem. 2003 Aug 29;278(35):33067-77 PMID: 12796505
  16. Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration.
    Biochem J. 2005 Oct 15;391(Pt 2):359-70 PMID: 15975092
  17. Activation of RhoB by hypoxia controls hypoxia-inducible factor-1alpha stabilization through glycogen synthase kinase-3 in U87 glioblastoma cells.
    Cancer Res. 2006 Jan 1;66(1):482-9 PMID: 16397264
  18. A molecular cell biology of lithium.
    Biochem Soc Trans. 2004 Nov;32(Pt 5):799-802 PMID: 15494019
  19. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion.
    Int J Biochem Cell Biol. 2004 Jun;36(6):1046-69 PMID: 15094120
  20. GSK-3: tricks of the trade for a multi-tasking kinase.
    J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86 PMID: 12615961
  21. Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme.
    Neuro Oncol. 2005 Apr;7(2):164-76 PMID: 15831234
  22. Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited.
    Mol Psychiatry. 2005 Jan;10(1):117-26 PMID: 15558078
  23. Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions.
    Cells Tissues Organs. 2007;185(1-3):73-84 PMID: 17587811
  24. A molecular mechanism for the effect of lithium on development.
    Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8455-9 PMID: 8710892
  25. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells.
    Curr Biol. 1996 Dec 1;6(12):1664-8 PMID: 8994831
  26. Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration.
    FEBS Lett. 1999 Jun 25;453(3):260-4 PMID: 10405156
  27. Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs.
    Neuropsychopharmacology. 2005 Jul;30(7):1223-37 PMID: 15827567
  28. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2.
    J Neuropathol Exp Neurol. 2005 Sep;64(9):754-62 PMID: 16141784
  29. The anti-proliferative effect of lithium chloride on melanoma cells and its reversion by myo-inositol.
    Br J Cancer. 1987 Jan;55(1):41-6 PMID: 3028460
  30. Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis.
    Lab Invest. 2005 Dec;85(12):1457-70 PMID: 16170333
  31. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.
    Chem Biol. 2000 Oct;7(10):793-803 PMID: 11033082
  32. Glycogen synthase kinase-3 regulates cytoskeleton and translocation of Rac1 in long cellular extensions of human keratinocytes.
    Exp Cell Res. 2004 Feb 1;293(1):68-80 PMID: 14729058
  33. Molecular mechanisms of glioma cell migration and invasion.
    J Neurooncol. 2004 Nov;70(2):217-28 PMID: 15674479
  34. Glycogen synthase kinase 3- and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement.
    Mol Cell Biol. 2006 Apr;26(7):2857-68 PMID: 16537926
  35. Glycogen synthase kinase 3beta phosphorylation of microtubule-associated protein 1B regulates the stability of microtubules in growth cones.
    J Cell Sci. 1999 Oct;112 ( Pt 19):3373-84 PMID: 10504342
  36. Cancer morbidity in psychiatric patients: influence of lithium carbonate treatment.
    Med Oncol. 1998 Apr;15(1):32-6 PMID: 9643528
  37. The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3beta and c-Jun/AP-1 signaling.
    FASEB J. 2005 Jan;19(1):144-6 PMID: 15507471
  38. GSK3 takes centre stage more than 20 years after its discovery.
    Biochem J. 2001 Oct 1;359(Pt 1):1-16 PMID: 11563964
  39. Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity.
    Nature. 2003 Feb 13;421(6924):753-6 PMID: 12610628
  40. Spheroid preparation from hanging drops: characterization of a model of brain tumor invasion.
    J Neurooncol. 2004 May;67(3):295-303 PMID: 15164985
  41. Molecular targets of lithium action.
    Annu Rev Pharmacol Toxicol. 2001;41:789-813 PMID: 11264477
  42. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics.
    Neurochem Res. 2007 Apr-May;32(4-5):577-95 PMID: 16944320
  43. SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions.
    Mol Cancer Res. 2004 Nov;2(11):595-605 PMID: 15561776
  44. GSK3beta-mediated phosphorylation of the microtubule-associated protein 2C (MAP2C) prevents microtubule bundling.
    Eur J Cell Biol. 2000 Apr;79(4):252-60 PMID: 10826493
  45. Lithium-mediated downregulation of PKB/Akt and cyclin E with growth inhibition in hepatocellular carcinoma cells.
    Int J Cancer. 2005 Jul 20;115(6):903-10 PMID: 15723355
Article Info
Journal
Neuro-oncology
Abbr.
Neuro Oncol
ISSN
1522-8517
DOI
10.1215/15228517-2008-041
Published
2008-10-00
Epub
2008-00-20
Pages
690-9
Language
English
Region
England
NLM ID
100887420
PMCID
PMC2666245
Subset
IM
Grants
NCI NIH HHS · R01 CA085139 · United States
External Links
PubMed source DOI: 10.1215/15228517-2008-041 PMC Full Text View journal details
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