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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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Project description:Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3β (glycogen synthase kinase-3β) activity and upregulating β-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.

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.

Similar Datasets

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