KG-135 inhibits COX-2 expression by blocking the activation of JNK and AP-1 in phorbol ester-stimulated human breast epithelial cells
KG-135 inhibits COX-2 expression by blocking the activation of JNK and AP-1 in phorbol ester-stimulated human breast epithelial cells
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DOI：
10.1196/annals.1397.059
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发表时间：
2007-01-01
期刊：
影响因子：
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通讯作者：
Surh, Young-Joon
中科院分区：
文献类型：
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作者：
Park, Sin-Aye;Kim, Eun-Hee;Surh, Young-Joon
人参皂苷是人参的主要成分，具有广泛的药理作用。特别是，来自热加工人参的人参皂苷Rk 1、Rg 3和Rg 5已显示出具有显著的抗肿瘤促进作用。KG-135是一种含有Rk 1、Rg 3、Rg 5、Rk 2、Rk 3、Rs3、Rs 4、Rs 5、Rs6、Rs7等多种抗肿瘤活性糖苷的复方制剂。本文旨在评价KG-135对人乳腺上皮细胞系MCF-10A的化学预防和抗炎作用。环氧合酶-2（考克斯-2）是公认的化学预防的分子靶点之一，其在许多癌前和恶性组织和细胞中异常上调。在这项研究中，我们发现KG-135抑制考克斯-2在MCF-10A细胞刺激的原型肿瘤促进剂12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）的表达。由于转录因子激活蛋白-1（AP-1）在肿瘤促进中起作用，并且还已知其调节考克斯-2诱导，因此我们试图确定KG-135对TPA诱导的AP-1激活的影响。与KG-135共处理导致TPA诱导的AP-1的DNA结合减少。此外，KG-135抑制TPA诱导的c-Jun N-末端激酶（JNK）磷酸化，该激酶调节MCF-10A细胞中的考克斯-2表达。JNK抑制剂SP 600125减弱TPA处理的MCF-10A细胞中考克斯-2的表达。综上所述，上述发现表明KG-135通过阻断JNK/AP-1信号通路抑制MCF-10A细胞中TPA诱导的考克斯-2表达。
Ginsenosides, ingredients of ginseng, have a wide array of pharmacologic effects. Especially, ginsenosides Rk1, Rg3, and Rg5 derived from heat-processed ginseng have been shown to possess substantial anti-tumor-promoting effects. KG-135 is a formulated complex that contains several antitumorigenic ginsenosides, such as Rk1, Rg3, Rg5, Rk2, Rk3, Rs3, Rs4, Rs5, Rs6, Rs7, etc. The present article was aimed at evaluating the chemopreventive as well as anti-inflammatory effects of KG-135 in the human breast epithelial cell line (MCF-10A). One of the well-recognized molecular targets for chemoprevention is cyclooxygenase-2 (COX-2) that is abnormally upregulated in many premalignant and malignant tissues and cells. In this study, we found that KG-135 inhibited COX-2 expression in MCF-10A cells stimulated with a prototype tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA). Since the transcription factor activator protein-1 (AP-1) plays a role in tumor promotion and is also known to regulate COX-2 induction, we attempted to determine the effect of KG-135 on TPA-induced activation of AP-1. Cotreatment with KG-135 resulted in a decrease in TPA-induced DNA binding of AP-1. In addition, KG-135 inhibited TPA-induced phosphorylation of c-Jun N-terminal kinases (JNK) that regulates COX-2 expression in MCF-10A cells. The JNK inhibitor SP600125 attenuated COX-2 expression in TPA-treated MCF-10A cells. Taken together, the above findings suggest that KG-135 inhibits TPA-induced COX-2 expression in MCF-10A cells by blocking the JNK/AP-1 signaling pathway.