STAT3 Inhibition as a Therapeutic Strategy for Chordoma.
STAT3 Inhibition as a Therapeutic Strategy for Chordoma.
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STAT3 抑制作为脊索瘤的治疗策略。
DOI：
10.1055/s-0036-1584198
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Sullivan,StephenE
中科院分区：
文献类型：
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作者：
Wang,AnthonyC;Owen,JohnH;Abuzeid,WaleedM;Hervey-Jumper,ShawnL;He,Xiaobing;Gurrea,Mikel;Lin,Meijuan;Altshuler,DavidB;Keep,RichardF;Prince,MarkE;Carey,ThomasE;Fan,Xing;McKean,ErinL;Sullivan,StephenE
信号转导和转录激活因子（STAT）蛋白调节关键的细胞命运决定，包括增殖和凋亡。STAT 3过表达在多种肿瘤中诱导肿瘤生长。STAT 3在脉络膜中被组成性激活，脉络膜是一种尽管进行了最大限度的手术和放射治疗仍具有高复发率的肿瘤。我们假设，一种新的小分子抑制剂的STAT 3（FLLL 32）将诱导显着的细胞毒性在骶骨和斜坡chorrhages.MethodsSacral（UCh 1）和斜坡（UM-CHOR-1）chorrhages. Cells细胞株生长在文化（后者来自原发性肿瘤外植体）。使用细胞活力测定优化FLLL 32给药参数。使用克隆增殖试验评估FLLL 32的抗肿瘤潜力。结果FLLL 32诱导UCh 1和UM-CHOR-1脉络膜细胞产生明显的细胞毒性，基本上消除了所有的活细胞，与FLLL 32给药后观察到的活化的磷酸化STAT 3下调相关。所观察到的细胞毒性的机制包括通过抑制有丝分裂增加细胞凋亡和减少细胞增殖。ConclusionAs a monetary therapy，FLLL 32在体外诱导来自颅底和骶骨的脉络膜细胞系的有效肿瘤杀伤。这种作用通过抑制STAT 3磷酸化、增加对凋亡的易感性和抑制细胞增殖来介导。
ObjectiveSignal transducer and activator of transcription (STAT) proteins regulate key cellular fate decisions including proliferation and apoptosis. STAT3 overexpression induces tumor growth in multiple neoplasms. STAT3 is constitutively activated in chordoma, a tumor with a high recurrence rate despite maximal surgical and radiation treatment. We hypothesized that a novel small molecule inhibitor of STAT3 (FLLL32) would induce significant cytotoxicity in sacral and clival chordoma cells.MethodsSacral (UCh1) and clival (UM-CHOR-1) chordoma cell lines were grown in culture (the latter derived from primary tumor explants). FLLL32 dosing parameters were optimized using cell viability assays. Antitumor potential of FLLL32 was assessed using clonal proliferation assays. Potential mechanisms underlying observed cytotoxicity were examined using immunofluorescence assays.ResultsFLLL32 induced significant cytotoxicity in UCh1 and UM-CHOR-1 chordoma cells, essentially eliminating all viable cells, correlating with observed downregulation in activated, phosphorylated STAT3 upon administration of FLLL32. Mechanisms underlying the observed cytotoxicity included increased apoptosis and reduced cellular proliferation through inhibition of mitosis.ConclusionAs a monotherapy, FLLL32 induces potent tumor kill in vitro in chordoma cell lines derived from skull base and sacrum. This effect is mediated through inhibition of STAT3 phosphorylation, increased susceptibility to apoptosis, and suppression of cell proliferation.