title: Efficacy of glycogen synthase kinase-3β targeting against osteosarcoma via activation of β-catenin.
abstract: Development of innovative more effective therapy is required for refractory osteosarcoma patients. We previously established that glycogen synthase kinase-3β (GSK- 3β) is a therapeutic target in various cancer types. In the present study, we explored the therapeutic efficacy of GSK-3β inhibition against osteosarcoma and the underlying molecular mechanisms in an orthotopic mouse model. Expression and phosphorylation of GSK-3β in osteosarcoma and normal osteoblast cell lines was examined, together with efficacy of GSK-3β inhibition on cell survival, proliferation and apoptosis and on the growth of orthotopically-transplanted human osteosarcoma in nude mice. We also investigated changes in expression, phosphorylation and co-transcriptional activity of β-catenin in osteosarcoma cells following GSK-3β inhibition. Expression of the active form of GSK- 3β (tyrosine 216-phosphorylated) was higher in osteosarcoma than osteoblast cells. Inhibition of GSK-3β activity by pharmacological inhibitors or of its expression by RNA interference suppressed proliferation of osteosarcoma cells and induced apoptosis. Treatment with GSK-3β-specific inhibitors attenuated the growth of orthotopic osteosaroma in mice. Inhibition of GSK-3β reduced phosphorylation at GSK- 3β-phospho-acceptor sites in β-catenin and increased β-catenin expression, nuclear localization and co-transcriptional activity. These results suggest the efficacy of GSK-3β inhibitors is associated with activation of β-catenin, a putative tumor suppressor in bone and soft tissue sarcoma and an important component of osteogenesis. Our study thereby demonstrates a critical role for GSK-3β in sustaining survival and proliferation of osteosarcoma cells, and identifies this kinase as a potential therapeutic target against osteosarcoma.
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.|Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Shingo
authors: S
authors: Shimozaki
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Norio
authors: N
authors: Yamamoto
authors: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Takahiro
authors: T
authors: Domoto
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Hideji
authors: H
authors: Nishida
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Katsuhiro
authors: K
authors: Hayashi
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Hiroaki
authors: H
authors: Kimura
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Akihiko
authors: A
authors: Takeuchi
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.|AntiCancer Incorporated, San Diego, CA, U.S.A.|Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Shinji
authors: S
authors: Miwa
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Kentaro
authors: K
authors: Igarashi
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Takashi
authors: T
authors: Kato
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Yu
authors: Y
authors: Aoki
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Takashi
authors: T
authors: Higuchi
authors: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Mayumi
authors: M
authors: Hirose
authors: Department of Surgery, University of California, San Diego, CA, U.S.A.|AntiCancer Incorporated, San Diego, CA, U.S.A.
authors: Robert M
authors: RM
authors: Hoffman
authors: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Toshinari
authors: T
authors: Minamoto
authors: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors: Hiroyuki
authors: H
authors: Tsuchiya
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: glycogen synthase kinase-3β; molecular target; orthotopic nude mice; osteosarcoma; treatment