Abrogation of constitutive STAT3 activity sensitizes human hepatoma cells to TRAIL-mediated apoptosis
Abrogation of constitutive STAT3 activity sensitizes human hepatoma cells to TRAIL-mediated apoptosis
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DOI：
10.1016/j.jhep.2007.04.017
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发表时间：
2007-10-01
影响因子：
25.7
通讯作者：
Eguchi, Katsumi
中科院分区：
文献类型：
--
作者：
Kusaba, Mariko;Nakao, Kazuhiko;Eguchi, Katsumi
背景/目的：STAT3 （Signal transducer and activator of transcription 3，信号换能器和激活因子）在多种癌细胞中被组成性激活，调控细胞生长和存活。我们研究了Janus激酶2特异性抑制剂AG490对人肝癌细胞的抗肿瘤作用。方法：观察AG490对Huh-1、Huh-7、HepG2和Hep3B细胞STAT3激活、细胞生长和存活以及细胞周期和凋亡相关蛋白表达的影响。接下来，在体外和体内检测AG490是否使肝癌细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）易感。结果：所有肝癌细胞均通过酪氨酸磷酸化检测到STAT3的组成性激活。AG490抑制STAT3的磷酸化及其活性。AG490通过下调细胞周期蛋白D1诱导Huh-1、Huh-7和HepG2细胞周期阻滞，诱导Hep3B细胞明显凋亡。AG490在所有肝癌细胞中下调至少一种抗凋亡蛋白Bcl-xL、survivin或XIAP。AG490使Huh-1、Huh-7和HepG2对trail诱导的细胞凋亡增敏。腹腔注射AG490， AG490与TRAIL联合使用对胸腺小鼠皮下Huh-7肿瘤生长的抑制作用更大。结论：AG490阻断STAT3的组成性激活，可增强TRAIL对人肝癌细胞的抗肿瘤活性。(C) 2007年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background/Aims: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and regulates cell growth and survival of various cancer cells. We investigated the anti-tumor effect of AG490, a Janus kinase 2 specific inhibitor, in human hepatoma cells.Methods: Effects of AG490 on STAT3 activation, on cell-growth and survival, and on the expression of cell-cycle- and apoptosis-related proteins were evaluated in Huh-1, Huh-7, HepG2 and Hep3B cells. Next, whether AG490 renders hepatoma cells susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was examined in vitro and in vivo.Results: Constitutively activated STAT3 through tyrosine phosphorylation was detected in all hepatoma cells. AG490 inhibited the phosphorylation of STAT3 and its activity. AG490 induced cell cycle arrest in Huh-1, Huh-7 and HepG2 through cyclin D1 downregulation, and induced marked apoptosis in Hep3B. AG490 downregulated at least one of the anti-apoptotic proteins, Bcl-xL, survivin or XIAP in all hepatoma cells. AG490 sensitized Huh-1, Huh-7 and HepG2 to TRAIL-induced apoptosis in vitro. Intraperitoneal injection of AG490, the combination of AG490 and TRAIL more greatly, repressed the growth of subcutaneous Huh-7 tumors in athymic mice.Conclusions: Abrogation of constitutive activation of STAT3 by AG490 enhances the anti-tumor activity of TRAIL against human hepatoma cells. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.