The involvement of Bax in zinc-induced mitochondrial apoptogenesis in malignant prostate cells.
The involvement of Bax in zinc-induced mitochondrial apoptogenesis in malignant prostate cells.
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BAX参与锌诱导的恶性前列腺细胞中的线粒体凋亡。
DOI：
10.1186/1476-4598-7-25
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发表时间：
2008-03-10
期刊：
影响因子：
37.3
通讯作者：
Costello, Leslie C.
中科院分区：
文献类型：
--
作者：
Feng, Pei;Li, Tieluo;Guan, Zhixin;Franklin, Renty B.;Costello, Leslie C.
前列腺癌的发展和进展需要正常的锌积累上皮细胞转化为失去锌积累能力的恶性细胞。这种代谢转化是必不可少的，这样锌的肿瘤抑制作用就可以消除，恶性过程就可以进行。锌的主要作用之一是通过诱导细胞凋亡来阻止前列腺细胞的生长。细胞锌的积累对线粒体有直接影响，导致细胞色素c的释放，细胞色素c启动导致细胞凋亡的半胱天冬酶级联反应。这种效应与线粒体孔形成过程有关，但锌诱导细胞色素c释放和诱导线粒体线粒体膜发生的机制尚未解决。本报告首次提供的信息，暗示Bax在锌诱导线粒体线粒体apoptogenesis。测定锌处理对PC-3细胞Bax水平和线粒体的影响。分离的线粒体暴露于锌导致膜结合Bax的增加，这是由于内源性常驻Bax的线粒体插入。线粒体Bax/Bcl-2比值在锌处理后升高。锌处理PC-3细胞也增加了线粒体Bax的水平。此外，锌处理增加了细胞Bax水平和细胞Bax/Bcl 2比值。Bax在PC-3细胞中的下调消除了锌诱导的凋亡。细胞Bax水平的增加似乎涉及锌诱导Bax基因表达。本报告扩展并证实了生理水平的锌诱导前列腺细胞凋亡。这项研究提供的证据表明，锌直接参与促进线粒体相关的孔形成过程，启动线粒体线粒体。这通过锌对增加Bax的细胞水平的额外作用而增强。为了避免锌的抗肿瘤致突变作用，前列腺癌中的恶性细胞会产生遗传/代谢适应，以防止锌的细胞积累。
The development and progression of prostate cancer requires the transformation of normal zinc-accumulating epithelial cells to malignant cells that have lost the ability to accumulate zinc. This metabolic transformation is essential so that the tumor suppressive effects of zinc can be eliminated and the malignant process can proceed. One of the major effects of zinc is its prevention of prostate cell growth by its induction of apoptosis. The accumulation of cellular zinc has a direct effect on the mitochondria that results in the release of cytochrome c, which initiates the caspase cascade that leads to apoptosis. This effect is associated with the mitochondrial pore-forming process, but the mechanism by which zinc induces the release of cytochrome c and induces mitochondrial apoptogenesis has not been resolved. The present report provides for the first time information that implicates Bax in the zinc induction of mitochondrial apoptogenesis. The effects of zinc treatment on the Bax levels of PC-3 cells and on the mitochondria were determined. The exposure of isolated mitochondria to zinc results in an increase in membrane bound Bax, which is due to the mitochondrial insertion of endogenous resident Bax. The mitochondrial Bax/Bcl-2 ratio is increased by zinc treatment. Zinc treatment of PC-3 cells also increases the mitochondrial level of Bax. In addition, zinc treatment increases the cellular level of Bax and the cellular Bax/Bcl2 ratio. Down regulation of Bax in PC-3 cells eliminates the zinc induction of apoptosis. The increase in cellular Bax level appears to involve zinc induction of Bax gene expression. This report extends and confirms that physiological levels of zinc induce apoptosis in prostate cells. The study provides evidence that zinc is directly involved in facilitating a Bax-associated pore formation process that initiates mitochondrial apoptogenesis. This is enhanced by an additional effect of zinc on increasing the cellular level of Bax. To avoid the anti-tumor apoptogenic effects of zinc, the malignant cells in prostate cancer posses genetic/metabolic adaptations that prevent the cellular accumulation of zinc.
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