title: Glycogen synthase kinase 3β sustains invasion of glioblastoma via the focal adhesion kinase, Rac1, and c-Jun N-terminal kinase-mediated pathway.
abstract: The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3β (GSK3β), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3β compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3β also contributes to the highly invasive nature of glioblastoma. The effects of GSK3β inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3β attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3β as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo- and radioresistance.
authors.affiliation: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Department of Hospital Pharmacy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Chikano
authors.affiliation: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Domoto
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Furuta
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Hemragul
authors.initials: H
authors.lastname: Sabit
authors.affiliation: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Department of Hospital Pharmacy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kitano-Tamura
authors.affiliation: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Ilya V
authors.initials: IV
authors.lastname: Pyko
authors.affiliation: Division of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Takino
authors.affiliation: Department of Hospital Pharmacy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Division of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Hospital Pharmacy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. mnakada@med.kanazawa-u.ac.jp minamoto@staff.kanazawa-u.ac.jp.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.affiliation: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. mnakada@med.kanazawa-u.ac.jp minamoto@staff.kanazawa-u.ac.jp.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Minamoto
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14; D020830:rac1 GTP-Binding Protein