Journal of Nutritional Biochemistry, 2010, 21(5):390-396.

Delayed activation of extracellular-signal-regulated kinase 1/2 is involved in genistein- and equol-induced cell proliferation and estrogen-receptor-α-mediated transcription in MCF-7 breast cancer cells

Huaqing Liu, Chunyan Hu, et al

The Key Laboratory of Reproductive Medicine of Jiangsu Province, Institute of Toxicology, Nanjing Medical University, Jiangsu, Nanjing, China; et al

The aim of this study was to determine whether the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway is involved in genistein- and equol-induced cell proliferation and estrogen receptor (ER) alpha transactivation. For MCF-7 human breast cells, low concentrations of genistein and equol enhanced proliferation and induced MCF-7 cells to enter the S-phase. Genistein- and equol-induced cell proliferation and S-phase entry were blocked by the ERalpha antagonists 4-hydroxytamoxifen and ICI 182,780 and by the mitogen-activated protein kinase 1/2 inhibitor U0126. These data indicated that ERalpha and mitogen-activated protein extracellular kinase/ERK signaling were required for the effects of genistein/equol on cell growth and cell cycle progression. Genistein and equol induced delayed and prolonged activation of ERK1/2. Inhibition of ERK1/2 phosphorylation by U0126 led to complete suppression of genistein- and equol-induced estrogen response element reporter activity and to suppression of the estrogen-responsive gene pS2. The anti-estrogen ICI had no effect on genistein- and equol-induced ERK1/2 phosphorylation. These results suggest that activation of ERK1/2 lies upstream of ER-mediated transcription, and that ERK1/2 activation is necessary for the transactivation of ERalpha. In conclusion, genistein and equol elicit a delayed activation of ERK1/2, and this activation appears to be involved in the proliferation of breast cancer cells and estrogen-dependent transcriptional activation.

美国《营养生物化学杂志》，2010年5月

在MCF-7 乳腺癌细胞中延迟激活的细胞外信号调节激酶 1/2 参与了金雀异黄素和雌马酚诱导的细胞增殖和雌激素受体 α 介导转录

刘华清，胡春燕等

中国南京医科大学毒理学研究所生殖医学重点实验室等

本研究的目的是确定细胞外信号调节激酶 1/2 (ERK1/2) 通路是否参与了金雀异黄素和雌马酚诱导的细胞增殖和雌激素受体 (ER) 阿尔法反式激活基因。对于人体乳腺癌细胞 MCF-7，低浓度的染料木素和雌马酚增强了细胞增殖并且诱导 MSF-7 细胞进入 S 期。金雀异黄素和雌马酚诱导的细胞增殖和 S 期的进入已被 ER-α-拮抗剂 4-羟基他莫昔芬和 ICI 182,780 以及有丝分裂激活的蛋白激酶 1/2 抑制剂 U0126阻止。这些数据表明，染料木黄酮/雌马酚对细胞生长及细胞周期进程起到作用需要ER-α和有丝分裂激活的蛋白激酶/ERK 细胞外信号。染料木素和雌马酚诱导了ERK1/2延迟和持续的活化。由 由U0126 抑制的ERK1/2 磷酸化导致了染料木黄酮和雌马酚诱导的雌激素响应活性的彻底镇压来抑制雌激素敏感基因 pS2。抗雌激素 ICI 对染料木黄酮和雌马酚诱导的 ERK1/2 磷酸化没有影响。这些结果表明ERK1/2的活化位于ER 介导转录的上游，并且 ERK1/2 活化是反式激活 ER -α基因的必要条件。总之，染料木素和雌马酚引起 了ERK1/2的延迟活化，这种活化似乎参与了乳腺癌细胞的扩散和雌激素依赖性转录的激活。