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首页> 外文期刊>Molecular cancer therapeutics >Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3.
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Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3.

机译：索拉非尼通过信号转导子和转录激活子的去磷酸化作用诱导人胶质母细胞瘤细胞的生长停滞和凋亡3。

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Glioblastoma is the most common type of primary brain tumor and is rapidly progressive with few treatment options. Here, we report that sorafenib (< or =10 micromol/L) inhibited cell proliferation and induced apoptosis in two established cell lines (U87 and U251) and two primary cultures (PBT015 and PBT022) from human glioblastomas. The effects of sorafenib on these tumor cells were associated with inhibiting phosphorylated signal transducers and activators of transcription 3 (STAT3; Tyr705). Expression of a constitutively activated STAT3 mutant partially blocked the effects of sorafenib, consistent with a role for STAT3 inhibition in the response to sorafenib. Phosphorylated Janus-activated kinase (JAK)1 was inhibited in U87 and U251 cells, whereas phosphorylated JAK2 was inhibited in primary cultures. Sodium vanadate, a general inhibitor of protein tyrosine phosphatases, blocked the inhibition of phosphorylation of STAT3 (Tyr705) induced by sorafenib. These data indicate that the inhibition of STAT3 activity by sorafenib involves both the inhibition of upstream kinases (JAK1 and JAK2) of STAT3 and increased phosphatase activity. Phosphorylation of AKT was also reduced by sorafenib. In contrast, mitogen-activated protein kinases were not consistently inhibited by sorafenib in these cells. Two key cyclins (D and E) and the antiapoptotic protein Mcl-1 were downregulated by sorafenib in both cell lines and primary cultures. Our data suggest that inhibition of STAT3 signaling by sorafenib contributes to growth arrest and induction of apoptosis in glioblastoma cells. These findings provide a rationale for potential treatment of malignant gliomas with sorafenib. Mol Cancer Ther; 9(4); 953-62. (c)2010 AACR.
机译：胶质母细胞瘤是最常见的原发性脑肿瘤类型，并且进展迅速，几乎没有治疗选择。在这里，我们报告索拉非尼（<或= 10 micromol / L）在人类胶质母细胞瘤的两个已建立细胞系（U87和U251）和两个原代培养物（PBT015和PBT022）中抑制细胞增殖并诱导凋亡。索拉非尼对这些肿瘤细胞的作用与抑制磷酸化信号转导子和转录激活子3（STAT3; Tyr705）有关。组成性激活的STAT3突变体的表达部分阻断了索拉非尼的作用，这与STAT3抑制作用对索拉非尼的作用一致。在U87和U251细胞中磷酸化的Janus激活激酶（JAK）1被抑制，而在原代培养物中磷酸化的JAK2被抑制。钒蛋白钠是蛋白质酪氨酸磷酸酶的一般抑制剂，它阻止了索拉非尼诱导的STAT3（Tyr705）磷酸化的抑制。这些数据表明索拉非尼对STAT3活性的抑制既包括对STAT3的上游激酶（JAK1和JAK2）的抑制，也包括磷酸酶活性的增加。索拉非尼还降低了AKT的磷酸化。相反，索拉非尼在这些细胞中不能持续抑制促分裂原活化的蛋白激酶。索拉非尼在细胞系和原代培养物中均下调了两个关键的细胞周期蛋白（D和E）和抗凋亡蛋白Mcl-1。我们的数据表明，索拉非尼对STAT3信号的抑制有助于胶质母细胞瘤细胞的生长停滞和凋亡诱导。这些发现为索拉非尼治疗恶性神经胶质瘤提供了理论依据。分子癌疗法; 9（4）; 953-62。 （c）2010年美国机管学会（AACR）。

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