Restoration of IRF1-dependent anticancer effects by MEK inhibition in human cancer cells
Restoration of IRF1-dependent anticancer effects by MEK inhibition in human cancer cells
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DOI：
10.1016/j.canlet.2014.12.017
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发表时间：
2015-02-28
期刊：
影响因子：
9.7
通讯作者：
Hirasawa, Kensuke
中科院分区：
文献类型：
--
作者：
AbuSara, Nader;Razavi, Seyd;Hirasawa, Kensuke
干扰素调节因子（IRF1）是一种有效的抗病毒、抗肿瘤和免疫调节蛋白。最近，我们发现激活的Ras/MEK通过下调IRF1表达抑制抗病毒反应，使癌细胞对溶瘤病毒易感。在这项研究中，我们试图确定IRF1下调是否在人类癌细胞中由Ras/MEK激活诱导的肿瘤发生中起作用。MEK抑制剂U0126在我们测试的11个癌细胞系中的7个中促进了IRF1的表达。在使用不同MEK抑制剂或针对细胞外信号调节激酶（ERKs）的RNAi寡核苷酸处理的人类癌细胞系中也观察到IRF1的促进。通过MEK抑制IRF1 shRNA敲除的癌细胞中抗肿瘤基因p27和p53上调的凋亡调节剂（PUMA）的表达比载体对照的癌细胞少，提示Ras/MEK靶向IRF1下调抗肿瘤基因。此外，U0126对IRF1 shRNA敲低细胞的凋亡诱导作用明显低于载体对照细胞。本研究表明，在人癌细胞中，IRF1的表达被激活的Ras/MEK抑制，IRF1在Ras/MEK抑制诱导的细胞凋亡中发挥重要作用。2014爱思唯尔爱尔兰有限公司版权所有。
Interferon regulatory factor (IRF1) is a potent antiviral, antitumor and immune regulatory protein. Recently, we found that activated Ras/MEK inhibits antiviral response by downregulating IRF1 expression and renders cancer cells susceptible to oncolytic viruses. In this study, we sought to determine whether IRF1 downregulation underlies oncogenesis induced by Ras/MEK activation in human cancer cells. Treatment of the MEK inhibitor U0126 promoted IRF1 expression in 7 of 11 cancer cell lines we tested. IRF1 promotion was also observed in human cancer cell lines treated with different MEK inhibitors or with RNAi oligonucleotides against extracellular signal-regulated kinases (ERKs). Restoration of the expression of antitumor genes, p27 and p53 upregulated modulator of apoptosis (PUMA), by MEK inhibition was less in IRF1 shRNA knockdown cancer cells than in vector control cancer cells, suggesting that Ras/MEK targets IRF1 for the downregulation of the antitumor genes. Moreover, apoptosis induction by U0126 was significantly reduced in IRF1 shRNA knockdown cells than vector control cells. This study demonstrates that IRF1 expression is suppressed by activated Ras/MEK in human cancer cells and that IRF1 plays essential roles in apoptosis induced by Ras/MEK inhibition. (C) 2014 Elsevier Ireland Ltd. All rights reserved.