Oncotarget

Research Papers:

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

Shingo Shimozaki, Norio Yamamoto, Takahiro Domoto, Hideji Nishida, Katsuhiro Hayashi, Hiroaki Kimura, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Takashi Kato, Yu Aoki, Takashi Higuchi, Mayumi Hirose, Robert M Hoffman _, Toshinari Minamoto and Hiroyuki Tsuchiya

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Oncotarget. 2016; 7:77038-77051. https://doi.org/10.18632/oncotarget.12781

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Abstract

Shingo Shimozaki1,4,*, Norio Yamamoto1, Takahiro Domoto4,*, Hideji Nishida1, Katsuhiro Hayashi1, Hiroaki Kimura1, Akihiko Takeuchi1, Shinji Miwa1,3,4, Kentaro Igarashi1, Takashi Kato1, Yu Aoki1, Takashi Higuchi1, Mayumi Hirose4, Robert M Hoffman2,3, Toshinari Minamoto4, Hiroyuki Tsuchiya1

1Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan

2Department of Surgery, University of California, San Diego, CA, U.S.A

3AntiCancer Incorporated, San Diego, CA, U.S.A

4Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

*These authors contributed equally to this work

Correspondence to:

Robert M. Hoffman, email: [email protected]

Norio Yamamoto, email: [email protected]

Keywords: glycogen synthase kinase-3β, molecular target, treatment, osteosarcoma, orthotopic nude mice

Received: September 09, 2016     Accepted: October 05, 2016     Published: October 20, 2016

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.


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