Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex
Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex
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DOI：
10.1016/j.fct.2012.12.017
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发表时间：
2013-05-01
影响因子：
4.3
通讯作者：
Cho, Youngsik
中科院分区：
文献类型：
--
作者：
Park, Seungyeon;Shin, Heesuk;Cho, Youngsik
当凋亡机制在肿瘤坏死因子α（TNF α）刺激期间受损或被阻断时，还提出了替代的细胞死亡程序性坏死。紫草素（SKN）是一种从中国植物中提取的草药，据报道，它可以诱导细胞凋亡或坏死，这取决于细胞类型或其浓度。在本研究中，SKN以剂量依赖性方式引起NIH 3 T3细胞死亡。有趣的是，SKN介导的细胞死亡部分受到necrostatin-1（Nec-1）的保护，Necrostatin-1是程序性坏死的特异性抑制剂，但不是泛半胱天冬酶抑制剂zVAD。SKN通过受体相互作用蛋白1和3（RIP 1-RIP 3）复合物的形成直接介导细胞死亡，这是TNF α介导的程序性坏死所必需的。此外，SKN引起的细胞死亡被活性氧（ROS）清除剂N-乙酰半胱氨酸（NAC）逆转，而TNF α介导的坏死被丁基羟基茴香醚（BHA）成功保护，这意味着ROS可能与死亡诱导剂不同。与活性氧清除剂或Nec-1对TNF α或SKN的保护作用同时，RIP 1-RIP 3复合物在这些物质的存在下受到显着影响。在这里，强调SKN以及TNF α可以通过促坏死复合物直接介导细胞死亡，但是ROS通过不同的途径产生，这取决于细胞死亡诱导剂。(C)2012爱思唯尔有限公司保留所有权利。
An alternative cell demise programmed necrosis has also been proposed when apoptotic machinery is impaired or blocked during tumor necrosis factor alpha (TNF alpha) stimulation. Shikonin (SKN), an herbal extract from the Chinese plant, has been reported to induce either apoptosis or necrosis depending on cell types or its concentrations. In this presentation, SKN caused cell death of NIH3T3 in a dose-dependent manner. Intriguingly, SKN-mediated cell death was in part protected by necrostatin-1 (Nec-1), a specific inhibitor of programmed necrosis, but not zVAD a pan-caspase inhibitor. SKN directly mediated cell death via receptor interacting protein1 and 3 (RIP1-RIP3) complex formation, which is required for TNF alpha-mediated programmed necrosis. Additionally, SKN-caused cell death was reversed by a reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) whereas TNF alpha-mediated necrosis was successfully protected by butylated hydroxyanisole (BHA), implying that ROS may be differentially derived from death inducing agents. Concurrently with the protective effect of the ROS scavenger or Nec-1 on TNF alpha or SKN, the RIP1-RIP3 complex was significantly affected in the presence of those agents. Here, it is high-lighted that SKN as well as TNF alpha can directly mediate cell death via a pronecrotic complex, but ROS were generated via different routes depending on cell death-inducing agents. (C) 2012 Elsevier Ltd. All rights reserved.