GPx2 counteracts PGE2 production by dampening COX-2 and mPGES-1 expression in human colon cancer cells
GPx2 counteracts PGE2 production by dampening COX-2 and mPGES-1 expression in human colon cancer cells
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DOI：
10.1089/ars.2008.2047
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发表时间：
2008-09-01
影响因子：
6.6
通讯作者：
Brigelius-Flohe, Regina
中科院分区：
文献类型：
--
作者：
Banning, Antje;Florian, Simone;Brigelius-Flohe, Regina
GPx2是一种胃肠道谷胱甘肽过氧化物酶，是一种主要在肠道中表达的硒蛋白。从GPx1和GPx2双敲除小鼠结肠炎和肠癌的发展中推断出抗炎和抗癌的潜力。此外，Nrf2激活剂的诱导将GPx2分类为保护酶。相反，增强的考克斯-2表达始终与炎症相关。GPx 2和考克斯-2的拮抗作用和有趣的共定位促使我们研究它们可能的相互调节。这两种酶在结直肠癌和结肠炎患者的组织中上调，并共同定位于内质网。在HT-29细胞中通过siRNA稳定敲低GPx 2导致考克斯-2和mPGES-1的高基础和IL-1诱导表达，所述酶是产生促炎性PGE 2所需的酶。因此，si-GPx2细胞释放高浓度的PGE2。所观察到的效应是GPx 2特异性的，因为考克斯-2和mPGES-1表达不受导致GPx 1消失的硒剥夺的影响。由此得出结论，GPx 2通过隔室化去除氢过氧化物沉默考克斯-2活性并抑制PGE 2依赖性考克斯-2表达。因此，GPx2可以防止对炎症刺激的过度反应，从而防止炎症驱动的致癌作用的启动。
GPx2, the gastrointestinal glutathione peroxidase, is a selenoprotein predominantly expressed in the intestine. An anti-inflammatory and anticarcinogenic potential has been inferred from the development of colitis and intestinal cancer in GPx1 and GPx2 double knockout mice. Further, induction by Nrf2 activators classifies GPx2 as a protective enzyme. In contrast, enhanced COX-2 expression is consistently associated with inflammation. The antagonistic roles and an intriguing co-localization of GPx2 and COX-2 prompted us to investigate their possible mutual regulation. Both enzymes were upregulated in tissues of patients with colorectal cancer and colitis, and co-localized in the endoplasmic reticulum. A stable knockdown of GPx2 in HT-29 cells by siRNA resulted in a high basal and IL-1-induced expression of COX-2 and mPGES-1, enzymes required for the production of the pro-inflammatory PGE2. Accordingly, si-GPx2 cells released high concentrations of PGE2. Observed effects were specific for GPx2, since COX-2 and mPGES-1 expression was not affected by selenium-deprivation which resulted in the disappearance of GPx1. It is concluded that GPx2 by compartmentalized removal of hydroperoxides silences COX-2 activity and suppresses PGE2-dependent COX-2 expression. Thus, GPx2 may prevent undue responses to inflammatory stimuli and, in consequence, inflammation-driven initiation of carcinogenesis.