S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2
S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2
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DOI：
10.1016/j.bbamcr.2007.10.015
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发表时间：
2008-02-01
影响因子：
5.1
通讯作者：
Los, Marek
中科院分区：
文献类型：
--
作者：
Ghavami, Saeld;Kerkhoff, Claus;Los, Marek
两个S 100 EF-手型钙结合蛋白S100 A8/A9的复合物诱导各种细胞，特别是肿瘤细胞的凋亡。使用几种细胞系，我们已经表明，S100 A8/A9诱导的细胞死亡是不介导的受体为晚期糖基化终产物（AGEs），受体先前证明从事S 100蛋白。对缺乏或过度表达死亡信号机制组分的细胞系的研究提供了对S100 A8/A9介导的细胞死亡途径的深入了解。用S100 A8/A9处理细胞引起线粒体膜电位（Δ Psi（m））的快速降低并激活巴克，但不引起凋亡诱导因子（AIF）、内切核酸酶G（Endo G）或细胞色素c的释放。然而，Smac/DIABLO和Omi/HtrA 2都选择性地释放到细胞质中，伴随着Drp 1表达的减少，这抑制了线粒体分裂机制。S100 A8/A9处理还导致抗凋亡蛋白Bcl 2和Bcl-1-X-L的表达降低，而促凋亡蛋白Bax、Bad和BNIP 3的表达没有改变。Bcl 2的过表达部分逆转了S100 A8/A9的细胞毒性。总之，这些数据表明，S100 A8/A9诱导的细胞死亡涉及巴克，选择性释放的Smac/DIABLO和Omi/HtrA 2从线粒体，和调节之间的平衡促和抗凋亡蛋白。(C)2007 Elsevier B. V.保留所有权利。
A complex of two S 100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S 100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (Delta Psi(m)) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bc1-X-L, whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and antiapoptotic proteins. (C) 2007 Elsevier B.V. All rights reserved.