PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death
PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death
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DOI：
10.1038/cdd.2012.35
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发表时间：
2012-09-01
影响因子：
12.4
通讯作者：
Horke, S. T.
中科院分区：
文献类型：
--
作者：
Schweikert, E-M;Devarajan, A.;Horke, S. T.
为了实现恶性，癌细胞转换了许多信号通路，逃避细胞死亡是一个特征标志。细胞死亡机制代表了一个抗癌靶标，需要不断识别肿瘤特异性信号分子。线粒体自由基形成的控制，特别是超氧化物将细胞死亡信号与适当的机制执行联系起来。超氧化物具有潜在的破坏性，但也会引发线粒体细胞色素c的释放。虽然对氧磷酶（PON）酶已知可预防心血管疾病，但最近的数据显示，PON2可减弱线粒体自由基的形成和细胞死亡的执行。另一个家族成员PON3的研究很少。利用不同的细胞培养系统和敲除小鼠，我们研究了它在癌症中的潜在作用。PON3在各种人类肿瘤中被发现过表达，并减少线粒体超氧化物的形成。它直接与辅酶Q10相互作用，可能通过隔离亚二醌起作用，导致细胞死亡抵抗能力增强。PON3定位于内质网（ER）和线粒体，在DNA损伤或内源性刺激而非外源性刺激时消除细胞凋亡。此外，PON3破坏内质网应激诱导的凋亡MAPK信号和CHOP诱导。因此，我们的研究揭示了PON3抗氧化作用的机制，并证明了PON3在肿瘤细胞发育中的先前未预料到的功能。我们认为pon代表了一类新的酶，对线粒体自由基的产生和细胞死亡起着至关重要的控制作用。细胞死亡与分化（2012）19,1549-1560；doi: 10.1038 / cdd.2012.35;2012年3月23日在线发布
To achieve malignancy, cancer cells convert numerous signaling pathways, with evasion from cell death being a characteristic hallmark. The cell death machinery represents an anti-cancer target demanding constant identification of tumor-specific signaling molecules. Control of mitochondrial radical formation, particularly superoxide interconnects cell death signals with appropriate mechanistic execution. Superoxide is potentially damaging, but also triggers mitochondrial cytochrome c release. While paraoxonase (PON) enzymes are known to protect against cardiovascular diseases, recent data revealed that PON2 attenuated mitochondrial radical formation and execution of cell death. Another family member, PON3, is poorly investigated. Using various cell culture systems and knockout mice, here we addressed its potential role in cancer. PON3 is found overexpressed in various human tumors and diminishes mitochondrial superoxide formation. It directly interacts with coenzyme Q10 and presumably acts by sequestering ubisemiquinone, leading to enhanced cell death resistance. Localized to the endoplasmic reticulum (ER) and mitochondria, PON3 abrogates apoptosis in response to DNA damage or intrinsic but not extrinsic stimulation. Moreover, PON3 impaired ER stress-induced apoptotic MAPK signaling and CHOP induction. Therefore, our study reveals the mechanism underlying PON3's anti-oxidative effect and demonstrates a previously unanticipated function in tumor cell development. We suggest PONs represent a novel class of enzymes crucially controlling mitochondrial radical generation and cell death. Cell Death and Differentiation (2012) 19, 1549-1560; doi:10.1038/cdd.2012.35; published online 23 March 2012