Butyrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition.
Butyrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition.
复制标题
DOI：
10.1016/j.bbrc.2004.03.066
复制
发表时间：
2004-04
影响因子：
3.1
通讯作者：
X. Tong;L. Yin;C. Giardina
中科院分区：
文献类型：
--
作者：
X. Tong;L. Yin;C. Giardina
Cox-2在结肠癌发生和炎症中发挥重要作用。以 HT-29 结肠癌细胞系为模型进行研究，我们发现 TNF-α 使 Cox-2 表达和活性增加约 25 倍。正如之前报道的其他 Cox-2 诱导剂一样，这种激活似乎是由于 p38 介导的 mRNA 稳定而不是启动子活性增加所致。 HDAC 抑制剂丁酸盐和 TSA 阻断 TNF-α 激活 Cox-2 蛋白和 mRNA 合成，并显着抑制 HT-29 细胞中的 Cox-2 活性。 Cox-2 合成的抑制不涉及启动子失活，甚至在 TNF-α 刺激后应用也能实现。 HDAC 抑制剂的作用是在 p21 表达激活之前观察到的，并且不需要新的蛋白质合成。最后，丁酸盐并不能阻止 p38 磷酸化，因此这种阻断很可能发生在激活途径的后续步骤。我们提出细胞因子诱导的 Cox-2 mRNA 稳定途径的一个组成部分对乙酰化敏感。
Cox-2 plays an important role in colon carcinogenesis and inflammation. Studying the HT-29 colon cancer cell line as a model, we found that Cox-2 expression and activity is increased approximately 25-fold by TNF-α. As previously reported for other Cox-2 inducers, this activation appears to result from a p38-mediated mRNA stabilization rather than an increase in promoter activity. The HDAC inhibitors butyrate and TSA blocked the TNF-α activation of Cox-2 protein and mRNA synthesis, and dramatically suppressed Cox-2 activity in HT-29 cells. The suppression of Cox-2 synthesis did not involve promoter inactivation and could be achieved even when applied after the TNF-α stimulus. The effect of the HDAC inhibitors was observed prior to the activation of p21 expression and did not require new protein synthesis. Finally, butyrate did not prevent p38 phosphorylation, so the block is likely to occur at a later step in the activation pathway. We propose that a component of the cytokine-induced Cox-2 mRNA stabilization pathway is sensitive to acetylation.