Cyclooxygenase-2/prostaglandin E2 pathway mediates icariside II induced apoptosis in human PC-3 prostate cancer cells
Cyclooxygenase-2/prostaglandin E2 pathway mediates icariside II induced apoptosis in human PC-3 prostate cancer cells
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DOI：
10.1016/j.canlet.2009.02.024
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发表时间：
2009-07-18
期刊：
影响因子：
9.7
通讯作者：
Kim, Sung-Hoon
中科院分区：
文献类型：
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作者：
Lee, Keun-Sung;Lee, Hyo-Jeong;Kim, Sung-Hoon
从朝鲜淫羊藿根中分离得到的淫羊藿苷II（IS）具有抗氧化活性，并能抑制黑素生成和缺氧诱导因子。我们在此首次报道IS通过其在PC-3前列腺癌细胞中的抗炎作用诱导细胞凋亡。IS对PC-3细胞具有细胞毒性，IC 50约为20 μ M。IS抑制PC-3细胞中组成型和花生四烯酸（AA）诱导的环氧合酶-2（考克斯-2）表达，并降低前列腺素E-2（PGE（2））水平，即使在低浓度（5和10 μ M）时也是如此。此外，IS增加亚G I凋亡部分，并在较高浓度（20和40 μ M）的PC-3细胞中显示末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）阳性凋亡小体。此外，IS还可降低PC-3细胞的线粒体膜电位，释放细胞色素C，激活caspase-9、-8和-3的表达，并裂解聚腺苷二磷酸核糖聚合酶（PARP）。一致的，考克斯-2，诱导型一氧化氮合酶（iNOS），血管内皮生长因子（VEGF）的表达被抑制，而在平行诱导凋亡的非依赖性前列腺癌细胞PC-3。此外，外源性PGE（2）抑制IS诱导的PC-3细胞PARP裂解，siRNA敲低考克斯-2可增强IS诱导的PARP裂解，提示考克斯-2通路在IS诱导的细胞凋亡中起重要作用。综上所述，这些发现表明IS作为一种有效的癌症化疗剂，在PC-3前列腺癌细胞中启动考克斯-2/PGE（2）通路的抑制，然后主要通过线粒体依赖性通路诱导凋亡。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Icariside II (IS) isolated from the roots of Epimedium koreanum Nakai was known to have antioxidant activity and inhibit melanogenesis and hypoxia inducible factor. We report here for the first time that IS induces apoptosis through its anti-inflammatory effects in PC-3 prostate cancer cells. IS exerted cytotoxicity against PC-3 cells with IC50 of approximately 20 mu M. IS suppressed both constitutive and arachidonic acid (AA)-induced cyclooxygenase-2 (COX-2) expression as well as reduced prostaglandin E-2 (PGE(2)) levels in PC-3 cells even at a low concentrations (5 and 10 mu M). Additionally, IS increased sub G I apoptotic portion and exhibited terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL)-positive apoptotic bodies in PC-3 cells at higher concentrations (20 and 40 mu M). Furthermore, IS attenuated the mitochondrial membrane potential, released cytochrome C into cytosol, activated caspase-9, -8, and -3 expressions and cleaved poly (ADPribose) polymerase (PARP) in PC-3 cells. Consistently, COX-2, inducible NO synthase (iNOS), and vascular endothelial growth factor (VEGF) expressions were suppressed while in parallel inducing apoptosis in hormone-independent prostate carcinoma cells PC-3. Moreover, exogeneous PGE(2) inhibited IS induced PARP cleavage in PC-3 cells and also knockdown of COX-2 by siRNA potentiated IS induced PARP cleavage, thereby implicating the critical role of COX-2 pathway in IS induced apoptosis. Taken together, these findings demonstrate that IS initiates the inhibition of COX-2/PGE(2) pathway and then induces apoptosis mainly via mitochondrial dependent pathway in PC-3 prostate cancer cells as a potent cancer chemotherapeutic agent. (C) 2009 Elsevier Ireland Ltd. All rights reserved.