Essential role of Stat3 in PI3K-induced oncogenic transformation
Essential role of Stat3 in PI3K-induced oncogenic transformation
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DOI：
10.1073/pnas.1110486108
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发表时间：
2011-08-09
影响因子：
11.1
通讯作者：
Vogt, Peter K.
中科院分区：
文献类型：
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作者：
Hart, Jonathan R.;Liao, Lujian;Vogt, Peter K.
由PI 3 K的p110 α-H1047 R突变体转化的细胞显示Stat 3的酪氨酸磷酸化增加。Stat 3的这种激活对于转化过程是重要的，因为Stat 3的显性负突变体干扰PI 3 K诱导的肿瘤发生。GDC-0941，一种PI 3 K的特异性抑制剂，降低Stat 3磷酸化水平。PI 3 K对Stat 3的作用似乎是由Tec激酶家族的成员介导的。Tec激酶抑制剂LFM-A13阻断H1047 R转化细胞中的Stat 3磷酸化。Janus激酶抑制剂AG 490和Src激酶抑制剂Src-1以及雷帕霉素对H1047 R转化细胞中的Stat 3磷酸化没有影响。H1047 R转化的细胞还释放一种因子，该因子在正常细胞中诱导Stat 3磷酸化，可能对细胞微环境产生影响。在一些人类肿瘤细胞系中，Stat 3的增强的磷酸化被PI 3 K和Tec激酶抑制剂抑制，表明PI 3 K和Stat 3之间的联系在人类癌症中是重要的。
Cells transformed by the p110 alpha-H1047R mutant of PI3K show increased tyrosine phosphorylation of Stat3. This activation of Stat3 is important for the transformation process, because a dominant-negative mutant of Stat3 interferes with PI3K-induced oncogenesis. GDC-0941, a specific inhibitor of PI3K reduces the level of Stat3 phosphorylation. The effect of PI3K on Stat3 appears to be mediated by a member of the Tec kinase family. The Tec kinase inhibitor LFM-A13 blocks Stat3 phosphorylation in H1047R-transformed cells. The Janus kinase inhibitor AG490 and the Src kinase inhibitor Src-1, as well as rapamycin, have no effect on Stat3 phosphorylation in H1047R-transformed cells. The H1047R-transformed cells also release a factor that induces Stat3 phosphorylation in normal cells with possible effects on the cellular microenvironment. In some human tumor cell lines, the enhanced phosphorylation of Stat3 is inhibited by both PI3K and by Tec kinase inhibitors, suggesting that the link between PI3K and Stat3 is significant in human cancer.