Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function.
Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function.
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DOI：
10.1371/journal.pone.0033656
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhou JR
中科院分区：
文献类型：
--
作者：
Gong Y;Li Y;Abdolmaleky HM;Li L;Zhou JR
本研究的目的是评价丹参中的丹参酮类化合物对乳腺癌细胞生长的影响，并阐明其细胞和分子作用机制。丹参酮类化合物在体外对乳腺癌细胞的生长抑制作用呈剂量依赖性，其中丹参酮I(T1)的抑制作用最强。T1也是唯一具有有效抑制三阴性乳腺癌细胞株MDA-MB231生长活性的丹参酮。T1诱导雌激素依赖和非雌激素依赖的细胞周期停滞与细胞周期蛋白D、CDK4和细胞周期蛋白B的改变有关，并诱导乳腺癌细胞的凋亡与c-PARP的上调和Survivin和Aurora A的下调有关。在乳腺肿瘤中也证实了Aurora A的过度表达。基因功能分析表明，Aurora A被siRNA敲除后，T1细胞的生长抑制和诱导凋亡活性显著降低，提示Aurora A是T1作用的重要功能靶点。另一方面，丹参酮对正常乳腺上皮细胞的不良影响要小得多。表观遗传学机制研究表明，Aurora A基因在乳腺癌细胞中的过表达不受基因启动子DNA甲基化的调控，而是受组蛋白乙酰化的调控。T1处理显著降低了与Aurora A基因相关的组蛋白H3的乙酰化水平。我们的结果支持T1在体外抑制乳腺癌细胞生长的有效活性，部分是通过下调Aurora A基因功能。我们以前的研究也证明了T1在体内具有强大的抗血管生成活性和最小的副作用。总之，这项研究值得进一步研究，以开发T1作为一种有效和安全的药物来治疗和预防乳腺癌。
The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen-dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer.
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6.1
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通讯作者：
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影响因子：
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