Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells
Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells
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DOI：
10.1007/s11060-010-0273-y
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发表时间：
2011-02-01
影响因子：
3.9
通讯作者：
Weissenberger, Jakob
中科院分区：
文献类型：
--
作者：
Senft, Christian;Priester, Maike;Weissenberger, Jakob
目前胶质母细胞瘤（GBM）的治疗策略的目标是细胞减灭。不幸的是，神经胶质肿瘤的有害迁移和侵袭行为在很大程度上仍然无人关注。已知转录因子信号转导子和转录激活子（STAT）3参与许多不同肿瘤类型（包括恶性胶质瘤）的发展和进展。除了其他生物学效应，STAT 3控制细胞增殖和组织重塑，这是伤口愈合和肿瘤扩散的共同过程。在这里，我们报告了5种不同的胶质母细胞瘤细胞系在用AG 490治疗后的迁移和侵袭潜力受到阻碍，AG 490是上游STAT 3激活剂Janus激酶（JAK）2的药理学抑制剂。STAT 3在所有测试的细胞系中被组成型激活，并且用AG 490处理以剂量依赖性方式消除了STAT 3的生物活性、酪氨酸705磷酸化形式，如通过Western印迹分析所确定的。通过酶谱法测定，STAT 3靶基因MMP-2和MMP-9的转录表达降低，从而抑制活化的STAT 3，并导致蛋白水解活性降低。因此，所有五种GBM细胞系的迁移行为在单层伤口愈合测定中受到阻碍;用AG 490处理也阻碍了基质胶包被的trans-well测定中的侵袭能力。用AG 490处理后，细胞系的增殖活性也显著降低。在PTEN表达细胞和PTEN缺陷细胞中均观察到STAT 3抑制引起的效应。由于JAK-2/STAT 3信号通路的药理学抑制不仅影响肿瘤细胞增殖，而且影响恶性胶质瘤的特征，即与恒定的肿瘤复发和高发病率相关的迁移和侵袭，我们的研究结果支持STAT 3是治疗脑肿瘤的合适靶点的想法。
The objective of current treatment strategies for glioblastoma (GBM) is cytoreduction. Unfortunately, the deleterious migratory and invasive behavior of glial tumors remains largely unattended. The transcription factor signal transducer and activator of transcription (STAT) 3 is known to be involved in the development and progression of many different tumor types, including malignant gliomas. Beside other biological effects, STAT3 controls cell proliferation and tissue remodeling, processes common to both wound healing and tumor dissemination. Here, we report on impeded migratory and invasive potential of five different glioblastoma cell lines after treatment with AG490, a pharmacological inhibitor of the upstream STAT3 activator Janus kinase (JAK) 2. STAT3 was constitutively activated in all the cell lines tested, and treatment with AG490 eliminated the biologically active, tyrosine705-phosphorylated form of STAT3 in a dose-dependent fashion, as determined by Western blot analysis. Inhibition of activated STAT3 was paralleled by a decrease in transcriptional expression of the STAT3 target genes MMP-2 and MMP-9, and led to reduced proteolytic activity, as determined by zymography. Accordingly, the migratory behavior of all five GBM cell lines was impeded in monolayer wound-healing assays; invasive capacity in matrigel-coated trans-well assays was also hampered by treatment with AG490. The proliferative activity of the cell lines was also significantly reduced after treatment with AG490. The effects elicited by STAT3 inhibition were observed in both PTEN-expressing and PTEN-deficient cells. Because pharmacological inhibition of the JAK-2/STAT3 signaling pathway affects not only tumor cell proliferation but also the characteristic features of malignant gliomas, i.e. migration and invasion pertinent to invariable tumor recurrence and high morbidity, our findings support the idea that STAT3 is a suitable target in the treatment of brain tumors.