HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells.
HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells.
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DOI：
10.1158/1535-7163.mct-09-0113
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发表时间：
2009-08
影响因子：
5.7
通讯作者：
Hazlehurst LA
中科院分区：
文献类型：
--
作者：
Nair RR;Emmons MF;Cress AE;Argilagos RF;Lam K;Kerr WT;Wang HG;Dalton WS;Hazlehurst LA
HYD 1是一种D-氨基酸肽，先前显示其抑制前列腺癌细胞与细胞外基质的粘附。在这项研究中，我们表明，除了抑制粘附多发性骨髓瘤（MM）细胞纤连蛋白，HYD 1诱导MM细胞作为一个单一的代理细胞死亡。HYD 1诱导的细胞死亡本质上是坏死性的，如以下所示：（a）线粒体膜电位（Δ Km）降低;（B）总细胞ATP损失;和（c）活性氧（ROS）产生增加。此外，HYD 1处理不会导致凋亡性细胞死亡，因为它不会触发半胱天冬酶的活化或线粒体中凋亡诱导因子（AIF）和内切核酸酶G（Endo G）的释放，也不会诱导双链DNA断裂。HYD 1确实在细胞中启动了自噬;然而，自噬被发现是一种有助于细胞存活的适应性反应，而不是细胞死亡的原因。我们还能够表明，N-乙酰基-L-半胱氨酸（NAC），一种含有巯基的自由基清除剂，部分保护MM细胞免受HYD 1诱导的死亡。此外，NAC阻断HYD 1诱导的自噬以及基础水平的自噬，表明ROS可以潜在地触发细胞死亡和细胞存活途径。总之，我们的数据描述了ROS在HYD 1诱导的MM细胞坏死性细胞死亡中的重要作用。
HYD1 is a D-amino acid peptide that was previously shown to inhibit adhesion of prostate cancer cells to the extracellular matrix. In this study, we show that in addition to inhibiting adhesion of multiple myeloma (MM) cells to fibronectin, HYD1 induces cell death in MM cells as a single agent. HYD1-induced cell death was necrotic in nature as shown by: (a) decrease in mitochondrial membrane potential (Δψm); (b) loss of total cellular ATP, and; (c) increase in reactive oxygen species (ROS) production. Moreover, HYD1 treatment does not result in apoptotic cell death as it did not trigger the activation of caspases or the release of apoptosis-inducing factor (AIF) and Endonuclease G (Endo G) from the mitochondria, nor did it induce double stranded DNA breaks. HYD1 did initiate autophagy in cells; however, autophagy was found to be an adaptive response contributing to cell survival rather than the cause of cell death. We were further able to show that N-acetyl-L-cysteine (NAC), a thiol containing free radical scavenger, partially protects MM cells from HYD1-induced death. Additionally NAC blocked HYD1- induced as well as basal levels of autophagy, suggesting that ROS can potentially trigger both cell death and cell survival pathways. Taken together, our data describe an important role of ROS in HYD1-induced necrotic cell death in MM cells.