Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells
Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells
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DOI：
10.1016/j.canlet.2008.11.029
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发表时间：
2009-05-18
期刊：
影响因子：
9.7
通讯作者：
Lee, Sang Kook
中科院分区：
文献类型：
--
作者：
Park, Eun-Jung;Min, Hye-Young;Lee, Sang Kook
和厚朴酚是一种天然存在的新木脂素，在厚朴中含量丰富，在多种人类癌细胞中显示出抗增殖和促凋亡的作用。然而，其抗肿瘤细胞增殖活性的分子机制还不是很清楚。在这项研究中，我们评估和厚朴酚对培养的雌激素受体(ER)阴性的人乳腺癌细胞MDA-MB-231的生长抑制活性。和厚朴酚具有抗增殖活性，使细胞周期停滞于G0/G1期，并以浓度依赖的方式诱导细胞凋亡。和厚朴酚诱导的细胞周期停滞与细胞周期蛋白CDK4、细胞周期蛋白D1、细胞周期蛋白CDK2、细胞周期蛋白E、c-Myc和磷酸化视网膜母细胞瘤蛋白(PRB)在Ser780的表达抑制密切相关。和厚朴酚诱导的细胞凋亡还伴随着caspase-3、-8、-9的切割和Bid的表达，同时抑制了Bcl2的表达，但不依赖于Bax和P53的表达。此外，和厚朴酚处理的细胞显示出聚腺苷二磷酸核糖聚合酶(PARP)的裂解和DNA片段化。在信号转导途径分析中，和厚朴酚下调c-Src、表皮生长因子受体(EGFR)和Akt的表达和磷酸化，从而导致mTOR及其下游信号分子4E结合蛋白(4E-BP)和p70 S6激酶失活。这些结果提示和厚朴酚对癌细胞生长的抑制作用可能与细胞周期停滞和通过信号转导途径诱导细胞凋亡有关。(C)2008爱思唯尔爱尔兰有限公司。保留所有权利。
Honokiol is a naturally occurring neolignan abundant in Magnoliae Cortex and has showed anti-proliferative and pro-apoptotic effects in a wide range of human cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells have been poorly elucidated. In this study, we evaluated the growth inhibitory activity of honokiol in cultured estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Honokiol exerted anti-proliferative activity with the cell cycle arrest at the G0/G1 phase and sequential induction of apoptotic cell death in a concentration-dependent manner. The honokiol-induced cell cycle arrest was well correlated with the suppressive expression of CDK4, cyclin D1, CDK2, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb) at Ser780. Apoptosis caused by honokiol was also concomitant with the cleavage of caspases (caspase-3, -8, and -9) and Bid along with the suppressive expression of Bcl-2, but it was independent on the expression of Bax and p53. In addition, honokiol-treated cells exhibited the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. In the analysis of signal transduction pathway, honokiol down-regulated the expression and phosphorylation of c-Src, epidermal growth factor receptor (EGFR), and Akt, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that honokiol-mediated inhibitory activity of cancer cell growth might be related with the cell cycle arrest and induction of apoptosis via modulating signal transduction pathways. (c) 2008 Elsevier Ireland Ltd. All rights reserved.