Fluacrypyrim, a novel STAT3 activation inhibitor, induces cell cycle arrest and apoptosis in cancer cells harboring constitutively-active STAT3
Fluacrypyrim, a novel STAT3 activation inhibitor, induces cell cycle arrest and apoptosis in cancer cells harboring constitutively-active STAT3
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Fluacrypyrim 是一种新型 STAT3 激活抑制剂，可诱导含有组成型活性 STAT3 的癌细胞的细胞周期停滞和细胞凋亡
DOI：
10.1002/ijc.25169
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发表时间：
2010-09-15
影响因子：
6.4
通讯作者：
Cong, Yu-Wen
中科院分区：
文献类型：
--
作者：
Yu, Zu-Yin;Huang, Rui;Cong, Yu-Wen
STAT 3蛋白在肿瘤发生中起重要作用，是一个很有前途的抗癌靶点。在此，我们证明了一种新的小分子氟吡嘧啶（FAPM）通过显著降低细胞周期蛋白D1的蛋白和mRNA水平的主要G1期阻滞来抑制白血病细胞的生长。由于青色D1是由STAT 3转录调节，FAPM则显示出显着抑制STAT 3磷酸化与边际效应的其他信号转导和转录激活剂，并没有影响磷酸肌醇-3-激酶和丝裂原活化蛋白激酶途径。进一步的分析表明，FAPM以剂量依赖性方式显著增加蛋白酪氨酸磷酸酶（PTP）的活性，过钒酸钠抑制PIP激活可逆转FAPM诱导的STAT 3酪氨酸磷酸化抑制，提示PTP在FAPM的作用中起重要作用。最后，FAPM处理导致选择性抑制STAT 3介导的转录活性及其下游效应物，并随后诱导STAT 3依赖性癌细胞系的生长停滞和凋亡。因此，本研究确定FAPM作为一种有效的STAT 3激活抑制剂，对具有组成性STAT 3激活的恶性肿瘤具有可能的治疗潜力。
STAT3 protein has an important role in oncogenesis and is a promising anticancer target. Herein, we demonstrate that a novel small molecule fluacrypyrim (FAPM) inhibits the growth of leukemia cells by a predominant G1 arrest with significant decrease of the protein and mRNA levels of cyclin Dl. As cyan D1 is transcriptionally regulated by STAT3, FAPM is then shown to markedly inhibit the STAT3 phosphorylation with marginal effect on the other signal transducers and activators of transcription, and without effect on phosphoinositide-3-kinase and mitogen-activated protein kinase pathways. Further analysis shows that FAPM significantly increases the protein tyrosine phosphatases (PTPs) activity in a dose-dependent manner, and the inhibition of PIP activation by sodium pervanadate reverses FAPM-induced suppression of STAT3 tyrosine phosphorylation, indicating an important role of PTP in the action of FAPM. Finally, FAPM treatment results in selective suppression of STAT3-mediated transcriptional activity and its downstream effectors, and subsequent induction of growth arrest and apoptosis in STAT3-dependent cancer cell lines. This study therefore identifies FAPM as a potent STAT3 activation inhibitor with possible therapeutic potential against malignancies with constitutive STAT3 activation.