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首页> 外文期刊>Molecular biology of the cell >Caveolin-1–mediated Suppression of Cyclooxygenase-2 via a β-catenin-Tcf/Lef–dependent Transcriptional Mechanism Reduced Prostaglandin E2 Production and Survivin Expression
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Caveolin-1–mediated Suppression of Cyclooxygenase-2 via a β-catenin-Tcf/Lef–dependent Transcriptional Mechanism Reduced Prostaglandin E2 Production and Survivin Expression

机译：Caveolin-1介导的β-catenin-Tcf/ Lef依赖性转录机制抑制环氧合酶-2降低前列腺素E2的产生和survivin的表达。

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Augmented expression of cyclooxygenase-2 (COX-2) and enhanced production of prostaglandin E2 (PGE2) are associated with increased tumor cell survival and malignancy. Caveolin-1 is a scaffold protein that has been proposed to function as a tumor suppressor in human cancer cells, although mechanisms underlying this ability remain controversial. Intriguingly, the possibility that caveolin-1 regulates the expression of COX-2 has not been explored. Here we show that augmented caveolin-1 expression in cells with low basal levels of this protein, such as human colon cancer (HT29, DLD-1), breast cancer (ZR75), and embryonic kidney (HEK293T) cells reduced COX-2 mRNA and protein levels and β-catenin-Tcf/Lef and COX-2 gene reporter activity, as well as the production of PGE2 and cell proliferation. Moreover, COX-2 overexpression or PGE2 supplementation increased levels of the inhibitor of apoptosis protein survivin by a transcriptional mechanism, as determined by PCR analysis, survivin gene reporter assays and Western blotting. Furthermore, addition of PGE2 to the medium prevented effects attributed to caveolin-1–mediated inhibition of β-catenin-Tcf/Lef–dependent transcription. Finally, PGE2 reduced the coimmunoprecipitation of caveolin-1 with β-catenin and their colocalization at the plasma membrane. Thus, by reducing COX-2 expression, caveolin-1 interrupts a feedback amplification loop involving PGE2-induced signaling events linked to β-catenin/Tcf/Lef–dependent transcription of tumor survival genes including cox-2 itself and survivin .
机译：环氧合酶-2（COX-2）的增强表达和前列腺素E 2 （PGE 2 ）的产生增加与肿瘤细胞的存活率和恶性程度有关。 Caveolin-1是一种支架蛋白，已被提议在人类癌细胞中起抑癌作用，尽管这种能力的潜在机制尚存争议。有趣的是，尚未探索caveolin-1调节COX-2表达的可能性。在这里，我们显示了在基础蛋白水平较低的细胞（例如人结肠癌（HT29，DLD-1），乳腺癌（ZR75）和胚胎肾（HEK293T）细胞）中，caveolin-1表达的增加降低了COX-2 mRNA的表达。蛋白质水平，β-catenin-Tcf/ Lef和COX-2基因报告子活性以及PGE 2 的产生和细胞增殖。此外，通过PCR分析，survivin基因报告基因分析和Western印迹分析，COX-2过表达或PGE 2 的补充通过转录机制增加了凋亡蛋白survivin抑制剂的水平。此外，在培养基中添加PGE 2 可防止归因于小窝蛋白1介导的抑制β-catenin-Tcf/ Lef依赖性转录的作用。最后，PGE 2 降低了Caveolin-1与β-catenin的共免疫沉淀作用以及它们在质膜上的共定位。因此，通过降低COX-2的表达，caveolin-1中断了一个涉及PGE 2 诱导的信号转导事件的反馈放大环，该信号转导与肿瘤生存基因的β-catenin/ Tcf / Lef依赖转录有关，包括cox- 2本身和survivin。

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