title: Regulation of glycogen synthase kinase-3 beta (GSK-3β) by the Akt pathway in gliomas.
abstract: Gliomas are aggressive brain tumours that, despite advances in multimodal therapies, continue to portend a dismal prognosis. Glioblastoma multiforme (GBM) represents the most aggressive glioma and patients have a median survival of 14 months, even with the best available treatments. The phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3 beta (GSK-3β) and Wnt/β-catenin pathways are dysregulated in a number of cancers, and these two pathways share a common node protein, GSK-3β. This protein is responsible for the regulation/degradation of β-catenin, which reduces β-catenin's translocation to the nucleus and influences the subsequent transcription of oncogenes. The non-specific small-molecule GSK-3β inhibitor, lithium chloride (LiCl), and the specific Akt inhibitor, AktX, were used to treat U87MG and U87MG.Δ2-7 human glioma cell lines. LiCl treatment significantly affected cell morphology of U87MG and U87MG.Δ2-7 cells, while also increasing levels of phospho-GSK-3β in a dose-dependent manner. Increased cell proliferation was observed at low-to-mid LiCl concentrations as determined by MTT cell growth assays. Treatment of U87MG and U87MG.Δ2-7 cells with AktX resulted in reduced levels of phospho-GSK-3β through its inhibition of Akt, in addition to decreased levels of phosphorylated (active) Akt in a dose-dependent fashion. We have shown in this study that GSK-3β regulation by phosphorylation is important for cell morphology and growth, and that LiCl enhances growth of U87MG and U87MG.Δ2-7 cells by inhibiting GSK-3β through its phosphorylation, whereas AktX reduces growth via activation of GSK-3β by inhibiting Akt's kinase activity.
authors.affiliation: Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Royal Parade, Parkville 3050, Victoria, Australia. ratkins@student.unimelb.edu.au
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Atkins
authors.forename: James
authors.initials: J
authors.lastname: Dimou
authors.forename: Lucy
authors.initials: L
authors.lastname: Paradiso
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morokoff
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Kaye
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Drummond
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hovens
mesh_terms: D015153:Blotting, Western; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004396:Coloring Agents; D066246:ErbB Receptors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005910:Glioma / Q000201:enzymology* / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000502:physiology*; D010766:Phosphorylation; D013778:Tetrazolium Salts; D013844:Thiazoles; D051153:Wnt Proteins / Q000096:biosynthesis
chemical_list: D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D051153:Wnt Proteins; D066246:ErbB Receptors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue; D018021:Lithium Chloride