Celastrol blocks interleukin-6 gene expression via downregulation of NF-κB in prostate carcinoma cells.
Celastrol blocks interleukin-6 gene expression via downregulation of NF-κB in prostate carcinoma cells.
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DOI：
10.1371/journal.pone.0093151
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Juang HH
中科院分区：
文献类型：
--
作者：
Chiang KC;Tsui KH;Chung LC;Yeh CN;Chen WT;Chang PL;Juang HH
白细胞介素-6（IL-6）是一种多功能细胞因子，以高度细胞类型特异性的方式促进前列腺癌细胞的增殖或分化。雷公藤红素（3-hydroxy-24-nor-2 oxo-1（10），3，5，7-friedelatetrane-29-oic acid），又名雷公藤红素（tripterine），是从传统中药雷公藤（Triplephyrumwilfordii Hook f）的根中提取的一种有效的抗炎、抗癌活性物质。本研究旨在探讨雷公藤红素对前列腺癌细胞增殖和IL-6基因表达的影响及其分子机制。3 H-TdR掺入和流式细胞仪分析表明雷公藤红素处理可使前列腺癌PC-3细胞周期阻滞于G 0/G1期，从而抑制细胞增殖;而且雷公藤红素在较高剂量下可诱导细胞凋亡。IL-6的敲低减弱雷公藤红素对PC-3细胞的抗增殖作用。ELISA和5 '-缺失瞬时基因表达分析的结果表明雷公藤红素处理降低了IL-6的分泌和基因表达，并且这种作用依赖于IL-6启动子区域内的NF-κ B反应元件，因为通过定点突变将NF-κB反应元件从AAATGTCCCATTTTCCC突变为AAATGTTACATTTTCCC消除了雷公藤红素对IL-6启动子活性的抑制。雷公藤红素还能减弱PMA和TNFα对PC-3细胞IL-6基因表达和分泌的激活作用。免疫印迹分析显示雷公藤红素处理下调IKKα、p50和p65的表达，支持5 '-缺失瞬时基因表达分析的结果，雷公藤红素通过NF-κB途径阻断PC-3细胞中IL-6的表达。我们的研究结果第一次得出结论，雷公藤红素通过NF-κ B依赖性途径下调IL-6基因表达来减弱PC-3细胞增殖。
Interleukin-6 (IL-6), a multifunctional cytokine, contributes to proliferation or differentiation of prostate carcinoma cells in a highly cell type-specific manner. Celastrol (3-hydroxy-24-nor-2oxo-1(10),3,5,7-friedelatetrane-29-oic acid), also named as tripterine, is extracted from root of Chinese traditional herb Tripterygiumwilfordii Hook f with potent anti-inflammatory and anti-cancer activities. In this study, we evaluated the molecular mechanisms of celastrol on cell proliferation and IL-6 gene expression in prostate carcinoma cells. 3H-thymidine incorporation and flow cytometric analysis indicated that celastrol treatments arrested the cell cycle at the G0/G1 phase, thus attenuating cell proliferation in prostate carcinoma PC-3 cells; moreover, celastrol induced cell apoptosis at higher dosage. Knockdown of IL-6 attenuated the anti-proliferative effect of celastrol on PC-3 cells. Results from ELISA and 5’-deletion transient gene expression assays indicated that celastrol treatment decreased IL-6 secretion and gene expression, and this effect is dependent on the NF-κB response element within IL-6 promoter area since mutation of the NF-κB response element from AAATGTCCCATTTTCCC to AAATGTTACATTTTCCC by site-directed mutagenesis abolished the inhibition of celastrol on the IL-6 promoter activity. Celastrol also attenuated the activation of PMA and TNFα on the gene expression and secretion of IL-6 in PC-3 cells. Immunoblot assays revealed that celastrol treatment downregulated the expressions of IKKα, p50 and p65, supporting the 5’-deletion transient gene expression assay result that celastrol blocked IL-6 expression through the NF-κB pathway in PC-3 cells. For the first time, our results concluded that celastrol attenuates PC-3 cell proliferation via downregulation of IL-6 gene expression through the NF-κB-dependent pathway.
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