Induction of DNA damage and ATF3 by retigeric acid B, a novel topoisomerase II inhibitor, promotes apoptosis in prostate cancer cells
Induction of DNA damage and ATF3 by retigeric acid B, a novel topoisomerase II inhibitor, promotes apoptosis in prostate cancer cells
复制标题
新型拓扑异构酶 II 抑制剂瑞替格酸 B 诱导 DNA 损伤和 ATF3，促进前列腺癌细胞凋亡
DOI：
10.1016/j.canlet.2013.05.022
复制
发表时间：
2013-08-28
期刊：
影响因子：
9.7
通讯作者：
Lou, Hongxiang
中科院分区：
文献类型：
--
作者：
Liu, Yongqing;Gao, Fengbin;Lou, Hongxiang
据报道，Retigeric Acid B (RB) 在体外和体内均表现出抗肿瘤活性。在这里，我们发现 RB 显着抑制拓扑异构酶 II α (Topo II α) 的活性，导致前列腺癌 (PCa) 细胞中显着的 DNA 损伤，强烈诱导 γ H2AX 和 DNA 片段化证明了这一点。 ATM 和 ATR 的激活依次导致磷酸化 Chk1/2 和磷酸化 Cdc25 响应 RB 的诱导。阻断 ATM/ATR 信号传导可导致 RB 诱导的 γ H2AX 减弱，并部分挽救 RB 介导的细胞死亡。 DNA 末端连接分析表明，RB 治疗还导致 DNA 修复蛋白（例如磷酸化 BRCA1）失活、HR 和 NHEJ 修复受损。与此同时，应激反应基因激活转录因子 3 (ATF3) 因其在 RB 诱导的 DNA 损伤中的主要表达而闻名。 ATF3的敲除抑制了RB诱导的细胞周期和细胞凋亡相关基因（例如DR5、DDIT4、CDC25A、GADD45A）的表达变化，并部分阻断了RB介导的对细胞增殖和细胞凋亡诱导的抑制，表明ATF3在此事件中发挥了关键作用。微阵列数据显示，RB 导致受损 DNA 结合和修复所需的基因以及 ATF3 及其靶基因发生变化。我们的数据首先证明 RB 是一种新型 DNA Topo II 抑制剂，并通过诱导 DNA 损伤和应激反应引发细胞死亡，这表明 RB 是一种有前途的抗癌剂。 (C) 2013 Elsevier Ireland Ltd. 保留所有权利。
Retigeric acid B (RB) has been reported to exhibit its anti-tumor activity in vitro and in vivo. Here, we found that RB significantly inhibited activity of topoisomerase II alpha (Topo II alpha), leading to remarkable DNA damage in prostate cancer (PCa) cells as evidenced by a strong induction of gamma H2AX and DNA fragmentation. Activation of ATM and ATR sequentially led to induction of phospho-Chk1/2 and phospho-Cdc25 in response to RB. Blockade of ATM/ATR signaling resulted in the attenuation of RB-induced gamma H2AX, and partially rescued RB-mediated cell death. RB treatment also resulted in inactivation of DNA repair proteins such as phospho-BRCA1, impairment of HR, and NHEJ repair as indicated by DNA end-joining assays. Meanwhile, a stress-responsive gene activating transcription factor 3 (ATF3) was noted for its predominant expression in response to RB-induced DNA damage. Knockdown of ATF3 inhibited the RB-induced expression changes of cell cycle- and apoptosis-related genes such as DR5, DDIT4, CDC25A, GADD45A, and partially blocked RB-mediated inhibition on cell proliferation and induction of apoptosis, suggesting the crucial involvement of ATF3 in this event. Microarray data displayed that RB caused changes of genes required for damaged-DNA binding and repair, as well as ATF3 and its target genes. Our data firstly demonstrated that RB was a novel DNA Topo II inhibitor and triggered cell death by inducing DNA damage and stress-response, suggesting a promising anticancer agent. (C) 2013 Elsevier Ireland Ltd. All rights reserved.