Ethanol extract of propolis and its constituent caffeic acid phenethyl ester inhibit breast cancer cells proliferation in inflammatory microenvironment by inhibiting TLR4 signal pathway and inducing apoptosis and autophagy.
Ethanol extract of propolis and its constituent caffeic acid phenethyl ester inhibit breast cancer cells proliferation in inflammatory microenvironment by inhibiting TLR4 signal pathway and inducing apoptosis and autophagy.
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蜂胶乙醇提取物及其成分咖啡酸苯乙酯通过抑制TLR4信号通路、诱导细胞凋亡和自噬抑制炎症微环境中乳腺癌细胞增殖
DOI：
10.1186/s12906-017-1984-9
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发表时间：
2017-09-26
影响因子：
--
通讯作者：
Xuan H
中科院分区：
文献类型：
--
作者：
Chang H;Wang Y;Yin X;Liu X;Xuan H
蜂胶及其主要成分咖啡酸苯乙酯(CAPE)具有良好的抗肿瘤和抗炎作用。然而，目前对蜂胶和CAPE在炎症微环境中对肿瘤的作用知之甚少，炎症反应在肿瘤发展的不同阶段起着决定性作用。为了解蜂胶乙醇提取物(EECP)及其主要成分CAPE对乳腺癌MDA-MB-231细胞Toll样受体4(TLR4)信号转导通路的影响及其机制。用1μg/mL脂多糖刺激80%融合的乳腺癌细胞。然后分别用CAPE(25μg/mL)和EECP(25、50和100μg/mL)处理细胞。用硫代罗丹明B法、化学法和划痕法测定细胞存活率、一氧化氮(NO)生成量和细胞迁移能力。免疫印迹法检测TLR4、MyD88、IRAK4、TRIF、caspase3、PARP、LC3B和P62的表达。免疫荧光显微镜检测TLR4、LC3B和核因子-κB p65(NF-κB p65)的表达。不同浓度的ECP(25、50、100μg/mL)和CAPE(25μg/mL)可显著抑制脂多糖刺激的MDAMB-231细胞的增殖、迁移和NO的产生。此外，EECP和CAPE激活caspase3和PARP诱导细胞凋亡，并上调Lc3-II和降低p62水平以诱导自噬。体外反搏和CAPE作用后，TLR4信号通路分子TLR4、MyD88、IRAK4、TRIF和NF-κBp65均下调。提示EECP及其主要成分CAPE通过激活细胞凋亡、自噬和抑制TLR4信号通路，在炎症微环境中抑制乳腺癌MDA-MB-231细胞增殖。EECP和CAPE在治疗炎症诱导的肿瘤方面有很好的应用前景。
Propolis and its major constituent – caffeic acid phenethyl ester (CAPE) have good abilities on antitumor and anti-inflammation. However, little is known about the actions of propolis and CAPE on tumor in inflammatory microenvironment, and inflammatory responses play decisive roles at different stages of tumor development. To understand the effects and mechanisms of ethanol-extracted Chinese propolis (EECP) and its major constituent - CAPE in inflammation-stimulated tumor, we investigated their effects on Toll-like receptor 4 (TLR4) signaling pathway which plays a crucial role in breast cancer MDA-MB-231 cell line. 80% confluent breast cancer MDA-MB-231 cells were stimulated with 1 μg/mL lipopolysaccaride (LPS). Then the cells were divided for treatment by CAPE (25 μg/mL) and EECP (25, 50 and 100 μg/mL), respectively. Cell viability, nitric oxide (NO) production and cell migration were measured by sulforhodamine B assay, chemical method and scratch assay. The levels of TLR4, MyD88, IRAK4, TRIF, caspase 3, PARP, LC3B and p62 were investigated through western blotting. The expression of TLR4, LC3B and nuclear factor-κB p65 (NF-κB p65) were tested by immunofluorescence microscopy assay. Treatment of different concentrations of EECP (25, 50 and 100 μg/mL) and CAPE (25 μg/mL) significantly inhibited LPS-stimulated MDA-MB-231 cell line proliferation, migration and NO production. Furthermore, EECP and CAPE activated caspase3 and PARP to induce cell apoptosis, and also upregulated LC3-II and decreased p62 level to induce autophagy during the process. TLR4 signaling pathway molecules such as TLR4, MyD88, IRAK4, TRIF and NF-κB p65 were all down-regulated after EECP and CAPE treatment in LPS-stimulated MDA-MB-231 cells. These findings indicated that EECP and its major constituent - CAPE inhibited breast cancer MDA-MB-231 cells proliferation in inflammatory microenvironment through activating apoptosis, autophagy and inhibiting TLR4 signaling pathway. EECP and CAPE may hold promising prospects in treating inflammation-induced tumor.
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