Direct effect of zinc on mitochondrial apoptogenesis in prostate cells
Direct effect of zinc on mitochondrial apoptogenesis in prostate cells
复制标题
DOI：
10.1002/pros.10128
复制
发表时间：
2002-09-01
期刊：
影响因子：
2.8
通讯作者：
Costello, LC
中科院分区：
文献类型：
--
作者：
Feng, P;Li, TL;Costello, LC
背景前列腺上皮细胞比其他哺乳动物细胞独特地积累显著更高水平的锌。我们以前的研究表明，在特定的前列腺细胞中，细胞内高水平锌的积累导致细胞凋亡的诱导和细胞生长的抑制。凋亡效应是由于锌诱导线粒体凋亡。我们现在报告进一步的研究证实了锌的这种作用，并提供了这种独特作用的机制。暴露于生理水平的锌对细胞凋亡的影响，确定了三个人前列腺细胞系（PC-3，BPH和HPR-1）。锌诱导的细胞凋亡通过DNA片段鉴定。测定锌对来自每个细胞系的分离的线粒体制备物的直接作用。细胞色素c的线粒体释放通过蛋白质印迹法测定。暴露于锌诱导PC-3和BPH细胞凋亡，但不在HPR-1细胞。PC-3和BPH细胞中锌积累量分别为4.3 ± 0.3和2.8 ± 0.4，高于HPR-1细胞中锌积累量（1.8 ± 0.1）。锌对PC-3细胞的凋亡作用早在4-6小时就可观察到，且这种作用是不可逆的。锌对PC-3和BPH细胞线粒体的影响与细胞色素c的释放有关，但对HPR-1细胞线粒体的影响不明显。暴露于锌诱导PC-3和BPH细胞的凋亡，其积累高水平的锌的细胞内，但不是在HPR-1细胞，其不积累高水平的锌。一旦启动，细胞凋亡的诱导不会被锌的去除逆转，即，这是一个不可逆转的过程。致突变作用是由于锌对线粒体的直接作用，导致细胞色素c的释放。锌诱导线粒体发生的细胞特异性取决于细胞积累高水平细胞内锌的能力和线粒体对锌的直接作用作出反应的能力。
BACKGROUND. Prostate epithelial cells uniquely accumulate significantly higher levels of zinc than other mammalian cells. We previously showed that the accumulation of high intracellular zinc levels in specific prostate cells results in the induction of apoptosis and the inhibition of cell growth. The apoptotic effect is due to zinc induction of mitochondrial apoptogenesis. We now report additional studies that corroborate this effect of zinc and provide insight into the mechanism of this unique effect.METHODS. The effect of exposure to physiological levels of zinc on apoptosis was determined for three human prostate cell lines (PC-3, BPH, and HPR-1). Zinc-induced apoptosis was identified by DNA fragmentation. The direct effect of zinc on isolated mitochondrial preparations from each cell line was determined. The mitochondrial release of cytochrome c was determined by Western blot.RESULTS. Exposure to zinc induced apoptosis in PC-3 and BPH cells but not in HPR-1 cells. The zinc accumulation in PC-3 (4.3 +/- 0.3) and BPH (2.8 +/- 0.4) was higher than that in HPR-1 cells (1.8 +/- 0.1). The apoptotic effect of zinc on PC-3 cells could be observed as early as 4-6 hr of zinc treatment, and this effect was not reversible. The exposure of isolated mitochondria from PC-3 and BPH cells to zinc resulted in the release of cytochrome c; but zinc had no effect on mitochondria from HPR-1 cells.CONCLUSIONS. Exposure to zinc induces apoptosis in PC-3 and BPH cells, which accumulate high intracellular levels of zinc, but not in HPR-1 cells, which do not accumulate high levels of zinc. Once initiated, the induction of apoptosis is not reversed by the removal of zinc, i.e., it is an irreversible process. The apoptogenic effect is due to a direct effect of zinc on mitochondria that results in the release of cytochrome c. The cell specificity of zinc induction of apoptogenesis is dependent on the ability of the cells to accumulate high levels of intracellular zinc and on the ability of the mitochondria to respond to the direct effect of zinc.