Gallic Acid Suppresses Lipopolysaccharide-Induced Nuclear Factor-κB Signaling by Preventing RelA Acetylation in A549 Lung Cancer Cells
Gallic Acid Suppresses Lipopolysaccharide-Induced Nuclear Factor-κB Signaling by Preventing RelA Acetylation in A549 Lung Cancer Cells
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DOI：
10.1158/1541-7786.mcr-09-0239
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发表时间：
2009-12-01
影响因子：
5.2
通讯作者：
Yoon, Ho-Geun
中科院分区：
文献类型：
--
作者：
Choi, Kyung-Chul;Lee, Yoo-Hyun;Yoon, Ho-Geun
虽然多项研究表明没食子酸在抑制恶性转化、肿瘤发展、炎症等方面具有重要作用，但没食子酸在炎症性疾病中的分子机制尚不清楚。在这项研究中，我们鉴定了来自Rosa rugosa的没食子酸是一种组蛋白乙酰转移酶（HAT）抑制剂，对大多数HAT酶具有全球特异性，但对表观遗传酶包括sirtuin（沉默交配型信息调控2同源物）1 （S. cerevisiae）、组蛋白去乙酰化酶和组蛋白甲基转移酶没有活性。酶动力学研究表明没食子酸非竞争性地抑制p300/ cbp依赖性HAT活性。我们发现，在A549肺癌细胞中，没食子酸抑制p300诱导的p65乙酰化，增加胞浆I κ B α水平，阻止脂多糖（LPS）诱导的p65易位到细胞核，抑制LPS诱导的核因子κ B活化。我们还表明，没食子酸处理抑制体内p65的乙酰化和lps诱导的血清白介素-6水平。重要的是，没食子酸通常抑制其他刺激引起的炎症反应，包括LIPS、ifn - γ和白细胞介素-1 β，并进一步下调核因子κ b调控的抗凋亡基因的表达。这些结果表明乙酰化在炎性疾病的发展中起着至关重要的作用。[j] .中国癌症杂志，2009;7(12):2011-21。
Although multiple studies have revealed that gallic acid plays an important role in the inhibition of malignant transformation, cancer development, and inflammation, the molecular mechanism of gallic acid in inflammatory diseases is still unclear. In this study, we identified gallic acid from Rosa rugosa as a histone acetyltransferase (HAT) inhibitor with global specificity for the majority of HAT enzymes, but with no activity toward epigenetic enzymes including sirtuin (silent mating type information regulation 2 homologue) 1 (S. cerevisiae), histone deacetylase, and histone methyltransferase. Enzyme kinetic studies indicated that gallic acid uncompetitively inhibits p300/CBP-dependent HAT activities. We found that gallic acid inhibits p300-induced p65 acetylation, both in vitro and in vivo, increases the level Of cytosoiic I kappa B alpha, prevents lipopolysaccharide (LPS)-induced p65 translocation to the nucleus, and suppresses LPS-induced nuclear factor-kappa B activation in A549 lung cancer cells. We have also shown that gallic acid treatment inhibits the acetylation of p65 and the LPS-induced serum levels of interleukin-6 in vivo. Importantly, gallic acid generally inhibited inflammatory responses caused by other stimuli, including LIPS, IFN-gamma, and interleukin-1 beta, and further downregulated the expression of nuclear factor-kappa B-regulated antiapoptotic genes. These results show the crucial role of acetylation in the development of inflammatory diseases. (Mol Cancer Res 2009;7(12):2011-21)