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Efficacy of glycogen synthase kinase-3? targeting against osteosarcoma via activation of ?-catenin.

ABSTRACT: Development of innovative more effective therapy is required for refractory osteosarcoma patients. We previously established that glycogen synthase kinase-3? (GSK- 3?) is a therapeutic target in various cancer types. In the present study, we explored the therapeutic efficacy of GSK-3? inhibition against osteosarcoma and the underlying molecular mechanisms in an orthotopic mouse model. Expression and phosphorylation of GSK-3? in osteosarcoma and normal osteoblast cell lines was examined, together with efficacy of GSK-3? 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 ?-catenin in osteosarcoma cells following GSK-3? inhibition. Expression of the active form of GSK- 3? (tyrosine 216-phosphorylated) was higher in osteosarcoma than osteoblast cells. Inhibition of GSK-3? activity by pharmacological inhibitors or of its expression by RNA interference suppressed proliferation of osteosarcoma cells and induced apoptosis. Treatment with GSK-3?-specific inhibitors attenuated the growth of orthotopic osteosaroma in mice. Inhibition of GSK-3? reduced phosphorylation at GSK- 3?-phospho-acceptor sites in ?-catenin and increased ?-catenin expression, nuclear localization and co-transcriptional activity. These results suggest the efficacy of GSK-3? inhibitors is associated with activation of ?-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-3? in sustaining survival and proliferation of osteosarcoma cells, and identifies this kinase as a potential therapeutic target against osteosarcoma.

SUBMITTER: Shimozaki S

PROVIDER: S-EPMC5363568 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Efficacy of glycogen synthase kinase-3β targeting against osteosarcoma via activation of β-catenin.

Shimozaki Shingo S Yamamoto Norio N Domoto Takahiro T Nishida Hideji H Hayashi Katsuhiro K Kimura Hiroaki H Takeuchi Akihiko A Miwa Shinji S Igarashi Kentaro K Kato Takashi T Aoki Yu Y Higuchi Takashi T Hirose Mayumi M Hoffman Robert M RM Minamoto Toshinari T Tsuchiya Hiroyuki H

Oncotarget 20161101 47

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 ...[more]

PMID: 27780915

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Dataset Information

Efficacy of glycogen synthase kinase-3? targeting against osteosarcoma via activation of ?-catenin.

Publications

Efficacy of glycogen synthase kinase-3β targeting against osteosarcoma via activation of β-catenin.

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