Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation.
Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation.
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DOI：
10.18632/oncotarget.14159
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发表时间：
2017-01-31
期刊：
影响因子：
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通讯作者：
Seliger C
中科院分区：
文献类型：
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作者：
Leidgens V;Proske J;Rauer L;Moeckel S;Renner K;Bogdahn U;Riemenschneider MJ;Proescholdt M;Vollmann-Zwerenz A;Hau P;Seliger C
胶质母细胞瘤（GBM）是最常见和恶性类型的原发性脑肿瘤，并与毁灭性的预后。STAT3是GBM的重要致病因子，Stattic可特异性抑制STAT3的表达。甲硫氨酸抑制GBM细胞增殖和迁移。来自其他肿瘤模型的证据表明，二甲双胍抑制STAT3，但没有关于脑肿瘤起始细胞（BTIC）的具体数据。我们研究了用Stattic、二甲双胍或其组合处理后7种BTIC及其分化的对应物（TC）的增殖和迁移。在器官型脑切片培养物上原位测量侵袭。使用Western印迹探索磷酸化和总STAT3的蛋白表达以及AMPK和mTOR信号传导。为了确定Stattic和二甲双胍抑制STAT3的功能相关性，我们在选定的BTIC中进行了STAT3的稳定敲入。用Stattic抑制STAT3降低了所有BTIC的增殖，但仅在7个TC中的4个中。BTIC和TC中的迁移和侵袭同样受到抑制。二甲双胍治疗降低了所有研究的BTIC和TC中的STAT3磷酸化。Stattic和二甲双胍联合治疗对BTIC增殖有显著的累加效应，但对迁移或侵袭无显著影响。未检测到对TC的累加效应。稳定的STAT3敲入部分减弱了Stattic和二甲双胍对BTIC的影响。总之，发现二甲双胍抑制BTIC和TC中的STAT3磷酸化。结合特异性和非特异性抑制STAT3可能代表一种有前途的治疗胶质母细胞瘤的新策略。
Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits GBM cell proliferation and migration. Evidence from other tumor models suggests that metformin inhibits STAT3, but there is no specific data on brain tumor initiating cells (BTICs). We explored proliferation and migration of 7 BTICs and their differentiated counterparts (TCs) after treatment with Stattic, metformin or the combination thereof. Invasion was measured in situ on organotypic brain slice cultures. Protein expression of phosphorylated and total STAT3, as well as AMPK and mTOR signaling were explored using Western blot. To determine functional relevance of STAT3 inhibition by Stattic and metformin, we performed a stable knock-in of STAT3 in selected BTICs. Inhibition of STAT3 with Stattic reduced proliferation in all BTICs, but only in 4 out of 7 TCs. Migration and invasion were equally inhibited in BTICs and TCs. Treatment with metformin reduced STAT3-phosphorylation in all investigated BTICs and TCs. Combined treatment with Stattic and metformin led to significant additive effects on BTIC proliferation, but not migration or invasion. No additive effects on TCs could be detected. Stable STAT3 knock-in partly attenuated the effects of Stattic and metformin on BTICs. In conclusion, metformin was found to inhibit STAT3-phosphorylation in BTICs and TCs. Combined specific and unspecific inhibition of STAT3 might represent a promising new strategy in the treatment of glioblastoma.