Phospholipase A2 Activity of Peroxiredoxin 6 Promotes Invasion and Metastasis of Lung Cancer Cells
Phospholipase A2 Activity of Peroxiredoxin 6 Promotes Invasion and Metastasis of Lung Cancer Cells
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DOI：
10.1158/1535-7163.mct-09-0904
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发表时间：
2010-04-01
影响因子：
5.7
通讯作者：
Um, Hong-Duck
中科院分区：
文献类型：
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作者：
Ho, Jin-Nyoung;Lee, Seung Bum;Um, Hong-Duck
过氧化物还原酶（Peroxiredoxins，PRDX）是一类巯基依赖性过氧化物酶。在该家族的六个哺乳动物成员中，PRDX 6是唯一额外表现出磷脂酶A（2）（PLA（2））活性的蛋白质。这个有趣的PRDX 6功能的生理作用目前在很大程度上是未知的。在这项研究中，我们发现PRDX 6增加了肺癌细胞的转移潜力。使用特异性药理学抑制剂和诱变研究对PRDX 6的酶活性进行功能分析，揭示了过氧化物酶和PLA（2）活性都是转移所需的。具体而言，过氧化物酶活性促进癌细胞的生长，而PLA（2）活性促进侵袭性。对后者的进一步研究表明，PLA（2）活性促进花生四烯酸的积累，花生四烯酸反过来诱导涉及p38激酶、磷酸肌醇3-激酶、Akt和尿激酶型纤溶酶原激活剂的侵入性途径。这项研究是第一个定义的功能PRDX 6的酶活性的转移，并显示花生四烯酸参与PRDX 6行动在完整的细胞。这些新的发现为阐明PRDX 6在癌症中的作用及其作用机制迈出了重要的一步。Mol Cancer Ther; 9（4）; 825-32. (C)2010年AACR。
Peroxiredoxins (PRDX) are a family of thiol-dependent peroxidases. Among the six mammalian members of this family, PRDX6 is the only protein that additionally exhibits phospholipase A(2) (PLA(2)) activity. The physiologic role of this interesting PRDX6 feature is largely unknown at present. In this study, we show that PRDX6 increases the metastatic potential of lung cancer cells. Functional analyses of the enzymatic activities of PRDX6, using specific pharmacologic inhibitors and mutagenesis studies, reveal that both peroxidase and PLA(2) activities are required for metastasis. Specifically, peroxidase activity facilitates the growth of cancer cells, and PLA(2) activity promotes invasiveness. Further investigation of the latter event discloses that PLA(2) activity promotes accumulation of arachidonic acid, which, in turn, induces the invasive pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and urokinase-type plasminogen activator. This study is the first to define the functions of the enzymatic activities of PRDX6 in metastasis and to show the involvement of arachidonic acid in PRDX6 action in intact cells. These novel findings provide a significant step toward elucidating the role of PRDX6 in cancer and the mechanism of its action. Mol Cancer Ther; 9(4); 825-32. (C) 2010 AACR.