Efficacy of glycogen synthase kinase-3β targeting against osteosarcoma via activation of β-catenin.
Efficacy of glycogen synthase kinase-3β targeting against osteosarcoma via activation of β-catenin.
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DOI：
10.18632/oncotarget.12781
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发表时间：
2016-11-22
期刊：
影响因子：
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通讯作者：
Tsuchiya H
中科院分区：
文献类型：
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作者：
Shimozaki S;Yamamoto N;Domoto T;Nishida H;Hayashi K;Kimura H;Takeuchi A;Miwa S;Igarashi K;Kato T;Aoki Y;Higuchi T;Hirose M;Hoffman RM;Minamoto T;Tsuchiya H
难治性骨肉瘤患者需要开发创新的更有效的治疗方法。我们先前确定糖原合成酶激酶-3 β（GSK- 3β）是各种癌症类型的治疗靶点。在本研究中，我们在原位小鼠模型中探索GSK-3β抑制剂对骨肉瘤的治疗效果和潜在的分子机制。检测GSK-3β在骨肉瘤和正常成骨细胞系中的表达和磷酸化，以及GSK-3β抑制对细胞存活、增殖和凋亡以及对裸鼠原位移植的人骨肉瘤生长的功效。我们还研究了GSK-3β抑制后骨肉瘤细胞中β-catenin的表达、磷酸化和共转录活性的变化。GSK- 3β活性形式（酪氨酸216磷酸化）在骨肉瘤中的表达高于成骨细胞。通过药理学抑制剂抑制GSK-3β活性或通过RNA干扰抑制其表达可抑制骨肉瘤细胞的增殖并诱导凋亡。GSK-3β特异性抑制剂治疗可减弱小鼠原位骨肉瘤的生长。GSK-3β的抑制减少了β-连环蛋白中GSK- 3β-磷酸受体位点的磷酸化，并增加了β-连环蛋白的表达、核定位和共转录活性。这些结果表明GSK-3β抑制剂的疗效与β-连环蛋白的活化相关，β-连环蛋白是骨和软组织肉瘤中的假定肿瘤抑制因子，也是骨生成的重要组分。因此，我们的研究证明了GSK-3β在维持骨肉瘤细胞的存活和增殖中的关键作用，并将该激酶确定为骨肉瘤的潜在治疗靶点。
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.