Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma
Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma
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DOI：
10.1111/cas.14271
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发表时间：
2019-12-30
期刊：
影响因子：
5.7
通讯作者：
Tsuchiya, Hiroyuki
中科院分区：
文献类型：
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作者：
Abe, Kensaku;Yamamoto, Norio;Tsuchiya, Hiroyuki
软组织肉瘤（STSs）是一种罕见的癌症类型。几乎一半的人对多管齐下的治疗没有反应，因此可能受益于生物靶向治疗。一个新兴的靶点是糖原合成酶激酶（GSK）3 β，它与包括癌症在内的多种疾病有关。在这里，我们研究了GSK3 β在滑膜肉瘤和纤维肉瘤中的表达、活性和可能的病理作用，包括骨科中遇到的大多数STS。活性形式的GSK3 β（酪氨酸216磷酸化）在滑膜肉瘤（SYO-1, HS-SY-II, SW982）和纤维肉瘤（HT1080）肿瘤细胞系中的表达高于未转化的成纤维细胞（NHDF），后者被认为是正常的间充质对位细胞。药理药物（AR-A014418, SB-216763）抑制GSK3 β活性或RNA干扰抑制其表达可抑制肉瘤细胞的增殖和胶原凝胶的侵袭，诱导肉瘤细胞凋亡。这些作用与G0/ g1期细胞周期阻滞和细胞周期蛋白D1、细胞周期蛋白依赖性激酶（CDK）4和基质金属蛋白酶2的表达降低有关。腹腔注射GSK3 β抑制剂可减弱胸腺小鼠SYO-1和HT1080异种移植物的生长，但无明显的有害影响。它还能减轻小鼠肿瘤细胞的增殖和诱导细胞凋亡。本研究表明，滑膜肉瘤和纤维肉瘤中GSK3 β活性的增加通过细胞周期蛋白D1/ cdk4介导的途径和增强的细胞外基质降解来维持肿瘤的增殖和侵袭。我们的研究结果为GSK3 β作为治疗这些STS类型的新靶点提供了生物学基础。
Soft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3 beta, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3 beta in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3 beta (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3 beta activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3 beta inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3 beta in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3 beta as a new and promising therapeutic target for these STS types.