Squalene Inhibits ATM-Dependent Signaling in γIR-Induced DNA Damage Response through Induction of Wip1 Phosphatase.
Squalene Inhibits ATM-Dependent Signaling in γIR-Induced DNA Damage Response through Induction of Wip1 Phosphatase.
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DOI：
10.1371/journal.pone.0147570
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Nishida H
中科院分区：
文献类型：
--
作者：
Tatewaki N;Konishi T;Nakajima Y;Nishida M;Saito M;Eitsuka T;Sakamaki T;Ikekawa N;Nishida H
共济失调性毛细血管扩张突变(ATM)激酶在细胞DNA损伤反应中起着重要的控制作用。ATM的抑制会导致检查点信号通路的抑制。因此，在抗癌治疗中加入检查点抑制剂可能是一种有效的靶向策略。最近的一项研究报道，Wip1是一种蛋白质磷酸酶，在DNA损伤反应中使ATM 1981的丝氨酸去磷酸化。角鲨烯已被提出用于补充抗癌治疗，如化疗和放射治疗；然而，几乎没有机制信息支持这一想法。在这里，我们报告了角鲨烯对ATM依赖的DNA损伤信号的抑制作用。角鲨烯本身不影响A549细胞的存活率和细胞周期，但增强了伽玛射线(γ-IR)的细胞毒作用。角鲨烯不改变ATM的体外激酶活性。然而，角鲨烯增加了细胞中Wip1的表达，并抑制了γIR处理的细胞中atm的激活。与角鲨烯对ATM的潜在抑制作用一致，角鲨烯处理细胞后，IR诱导的ATM效应分子P53(Ser15)和Chk1(Ser317)的磷酸化被抑制。因此，角鲨烯通过在细胞内诱导Wip1的表达来抑制DNA损伤后依赖ATM的信号通路。
Ataxia telangiectasia mutated (ATM) kinase plays a crucial role as a master controller in the cellular DNA damage response. Inhibition of ATM leads to inhibition of the checkpoint signaling pathway. Hence, addition of checkpoint inhibitors to anticancer therapies may be an effective targeting strategy. A recent study reported that Wip1, a protein phosphatase, de-phosphorylates serine 1981 of ATM during the DNA damage response. Squalene has been proposed to complement anticancer therapies such as chemotherapy and radiotherapy; however, there is little mechanistic information supporting this idea. Here, we report the inhibitory effect of squalene on ATM-dependent DNA damage signals. Squalene itself did not affect cell viability and the cell cycle of A549 cells, but it enhanced the cytotoxicity of gamma-irradiation (γIR). The in vitro kinase activity of ATM was not altered by squalene. However, squalene increased Wip1 expression in cells and suppressed ATM activation in γIR-treated cells. Consistent with the potential inhibition of ATM by squalene, IR-induced phosphorylation of ATM effectors such as p53 (Ser15) and Chk1 (Ser317) was inhibited by cell treatment with squalene. Thus, squalene inhibits the ATM-dependent signaling pathway following DNA damage through intracellular induction of Wip1 expression.