title: Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma.
abstract: OBJECTIVE
  Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3beta (GSK3beta), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma.
  
  
  METHODS
  The active fraction of GSK3beta that is phosphorylated at the tyrosine 216 residue (pGSK3betaY216) was identified in glioblastoma cell lines. GSK3beta activity for phosphorylating its substrate was detected in these cells by nonradioisotopic in vitro kinase assay.
  
  
  RESULTS
  Higher expression levels of GSK3beta and pGSK3betaY216 were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3beta activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells in vitro. Inhibition of GSK3beta was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type p53 and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation.
  
  
  CONCLUSIONS
  These results indicate that GSK3beta exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways. Consequently, we propose that GSK3beta provides a potential therapeutic target in glioblastoma.
authors.affiliation: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Miyashita
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kawakami
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.forename: Wei
authors.initials: W
authors.lastname: Mai
authors.forename: Abbas
authors.initials: A
authors.lastname: Shakoori
authors.forename: Hironori
authors.initials: H
authors.lastname: Fujisawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Hamada
authors.forename: Toshinari
authors.initials: T
authors.lastname: Minamoto
mesh_terms: D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D034622:RNA Interference; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D011838:Radiation-Sensitizing Agents; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3