2-methoxyestradiol induces cell cycle arrest and mitotic cell apoptosis in human vascular smooth muscle cells
2-methoxyestradiol induces cell cycle arrest and mitotic cell apoptosis in human vascular smooth muscle cells
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DOI：
10.1161/01.hyp.0000199656.99448.dc
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发表时间：
2006-02-01
期刊：
影响因子：
8.3
通讯作者：
Zheng, XL
中科院分区：
文献类型：
--
作者：
Gui, Y;Zheng, XL
已有研究表明，2-甲氧基雌二醇(2-ME)可抑制人主动脉平滑肌细胞的增殖和DNA合成。然而，2-ME抗增殖活性的细胞机制尚不清楚。本研究旨在探讨2-ME诱导人血管平滑肌细胞生长抑制和凋亡的细胞机制。结果表明，在处理1h时，1mU/L 2-ME可诱导多个纺锤体、中心体过度放大和多极胞质分裂，而10mU/L 2-ME可导致纺锤体完全破坏、中心体定向紊乱和染色体错误分离。处理6h后，有丝分裂指数增加并达到最大值，4N DNA含量的细胞(4N细胞)开始聚集。2-ME诱导的细胞有丝分裂增加，Annexin V和TUNEL染色均显示为凋亡细胞。胸腺嘧啶核苷阻断G(1/0)期细胞可阻止2-ME诱导的细胞凋亡。此外，在10 mU/L 2-ME作用12~48小时后，增加的4N细胞数同时下降。此外，作为对2-ME的反应，细胞延迟进入下一个细胞周期，并表现出非整倍体或微核。一些非整倍体细胞继续合成DNA。我们的结论是，2-ME处理不仅阻止了细胞的有丝分裂，促进了有丝分裂细胞的凋亡，而且还使细胞经历了有丝分裂滑移和内复制。诱导有丝分裂细胞停滞和凋亡可能是2-ME抑制人血管平滑肌细胞增殖的主要细胞机制。
It has been shown that 2-methoxyestradiol (2-ME) inhibits cell proliferation and DNA synthesis in human aortic smooth muscle cells. However, the cellular mechanisms underlying the antiproliferative activity of 2-ME are unclear. The present study was performed to explore the cellular mechanisms whereby 2-ME leads to growth inhibition and apoptosis of human smooth muscle cells. Our results demonstrate that at 1 hour of treatment, 1 mu mol/L 2-ME induces multiple spindles, overamplified centrosomes, and multipolar cytokinesis, whereas 10 mu mol/L 2-ME causes completely damaged spindle, disorientated centrosomes, and missegregated chromosomes. At 6 hours of treatment, the mitotic index was increased and reached a maximal level, and cells with 4N DNA content ( 4N cells) began to accumulate. The increased mitotic cells induced by 2-ME were apoptotic as detected by both annexin V and TUNEL staining. Blockage of cells in G(1/0) phase by thymidine prevented 2-ME-induced apoptosis. In addition, the increased mitotic index declined concurrently when even more 4N cells accumulated at 12 to 48 hours of treatment with 10 mu mol/ L 2-ME. Furthermore, in response to 2-ME, cells delayed entry into the next cell cycle and exhibited aneuploidy or micronuclei. Some aneuploidy cells continued to synthesize DNA. We conclude that 2-ME treatment not only arrests cells in mitosis and promotes mitotic cell apoptosis, but also causes cells to undergo "mitotic slippage" and endoreduplication. The induction of mitotic cell arrest and apoptosis may be a major cellular mechanism by which 2-ME inhibits proliferation of human smooth muscle cells.