2-Methoxyestradiol blocks cell-cycle progression at G2/M phase and inhibits growth of human prostate cancer cells
2-Methoxyestradiol blocks cell-cycle progression at G2/M phase and inhibits growth of human prostate cancer cells
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DOI：
10.1002/mc.1046
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发表时间：
2001-07-01
影响因子：
4.6
通讯作者：
Slaga, TJ
中科院分区：
文献类型：
--
作者：
Kumar, AP;Garcia, GE;Slaga, TJ
2-甲氧雌二醇（2-ME）是17 β-雌二醇的内源性代谢产物，存在于人体血液和尿液中。我们首次发现2-ME能显著抑制正常前列腺上皮细胞、雄激素依赖性LNCaP和非氢依赖性前列腺癌细胞DU 145的生长。细胞周期分析显示，这种生长抑制伴随着G（2）/M群的两倍增加，同时伴随着G（1）群的减少。2-ME处理通过阻断前列腺癌细胞的G（2）期而影响细胞周期进程。对G（2）/M期关键细胞周期调节蛋白的免疫印迹分析显示，p21的表达增加了14倍，p34细胞分裂周期2（cdc 2）的表达增加了8倍。2-ME处理后，我们还发现了磷酸化cdc 2的积累。此外，Wee I激酶在2-ME处理后可检测到。用末端脱氧核苷酸转移酶介导的脱氧尿苷5-三磷酸-生物素缺口末端标记和荧光素异硫氰酸酯-聚（ADP-核糖）聚合酶分析表明，2-ME处理还导致caspase-3活性增加，随后细胞凋亡。雌激素受体水平没有改变治疗后与2-ME。检查的信号通路，介导2-ME诱导的细胞凋亡显示p53的表达水平和DNA结合活性的减少。鉴于p53突变在转移性前列腺癌患者中很常见，我们发现2-ME介导的人前列腺癌细胞生长抑制以p53非依赖性方式发生具有相当大的临床意义。这些发现，结合2-ME的有限毒性，可能对晚期前列腺癌的替代治疗具有重要意义。(C)2001 Wiley-Liss，Inc.
2-Methoxyestradiol (2-ME), an endogenous metabolite of 17 beta -estradiol, is present in human blood and urine. Here we show for the first time that 2-ME significantly inhibited the growth of normal prostate epithelial cells and androgen-dependent LNCaP and an drogen-independent DU145 prostate cancer cells, This growth Inhibition was accompanied by a twofold increase in the G(2)/M Population, with a concomitant decrease in the G(1) population, as shown by cell-cycle analysis. 2-ME treatment affected the cell-cycle progression of prostate cancer cells specifically by blocking cells In the G(2) phase. Immunoblot analysis of the key cell-cycle regulatory proteins In the G(2)/M phase showed a 14-fold increase In the expression of p21 and an eightfold increase in the expression of p34 cell division cycle 2 (cdc2). We also found an accumulation of phosphorylated cdc2 after 2-ME treatment. Furthermore, Wee I kinase was detectable after 2-ME treatment. 2-ME treatment also led to an increase In the activity of caspase-3, followed by apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick end-labeling and fluorescein isothiocyanate-poly(ADP-ribose) polymerase assay. Estrogen receptor levels did not change after treatment with 2-ME. Examination of the signaling pathways that mediate 2-ME-induced apoptosis showed reduction in the level of p53 expression and its DNA-binding activity. Given the fact that p53 mutations are common in patients with metastatic prostate cancer, our finding that 2-ME-mediated growth inhibition of human prostate cancer cells occurred in a p53-independent manner has considerable clinical significance. These findings, combined with the limited toxicity of 2-ME, may have significant implications for alternative treatment of advanced prostate cancer. (C) 2001 Wiley-Liss, Inc.