Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Int J Cancer. 2010 Sep 1;127(6):1259-70. doi: 10.1002/ijc.25169.
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 D1. As cyclin 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 PTP 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.
STAT3 蛋白在肿瘤发生中具有重要作用，是一种有前途的抗癌靶点。本文证明，新型小分子氟丙烯嘧啶（FAPM）通过主要的 G1 期阻滞抑制白血病细胞的生长，细胞周期蛋白 D1 的蛋白和 mRNA 水平显著下降。由于 cyclin D1 受 STAT3 转录调控，FAPM 可显著抑制 STAT3 磷酸化，对其他信号转导和转录激活物的影响较小，对磷酸肌醇 3-激酶和丝裂原活化蛋白激酶途径无影响。进一步分析表明，FAPM 以剂量依赖的方式显著增加蛋白酪氨酸磷酸酶（PTPs）的活性，而过氧化氢钠抑制 PTP 激活可逆转 FAPM 诱导的 STAT3 酪氨酸磷酸化抑制，表明 PTP 在 FAPM 作用中起重要作用。最后，FAPM 处理导致 STAT3 介导的转录活性及其下游效应物的选择性抑制，并随后诱导 STAT3 依赖性癌细胞系的生长停滞和凋亡。因此，本研究将 FAPM 鉴定为一种有效的 STAT3 激活抑制剂，可能对具有组成性 STAT3 激活的恶性肿瘤具有治疗潜力。
