A low concentration of genistein induces estrogen receptor-alpha and insulin-like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells
A low concentration of genistein induces estrogen receptor-alpha and insulin-like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells
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DOI：
10.1093/humrep/den087
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发表时间：
2008-08-01
影响因子：
6.1
通讯作者：
Dixon, D.
中科院分区：
文献类型：
--
作者：
Di, X.;Yu, L.;Dixon, D.
背景：以前，我们发现低浓度的染料木黄酮会刺激人子宫平滑肌瘤（LM）细胞的生长，而不是子宫平滑肌（肌层）细胞（SMC）。这项研究的目的是了解染料木黄酮会导致LM细胞过度增殖的分子机制。方法：使用雌激素反应元件基因报告基因，实时RT-PCR，Western印迹，免疫沉淀和细胞增殖测定法评估了染料木黄酮对LM细胞和SMC的染料木黄酮对LM细胞和SMC的影响。结果：发现雌激素受体（ER）反式激活，早期雌激素反应性基因的mRNA表达增加，孕酮受体和胰岛素样生长因子-I（IGF-I）以及ER-α（ERα）的蛋白质水平降低在染料木黄酮处理的LM细胞中，而不是SMC。此外，瞬时激活了细胞外调节激酶（ERK），SRC同源性/胶原蛋白（SHC）和ERα，ERα和IGF-I受体（IGF-IR）之间的相互作用被LM细胞中的Genastein迅速诱导。使用ER拮抗剂ICI 182,780和MAPK/ERK激酶（MEK）抑制剂PD98059，我们发现这些早期事件受到抑制，并且染料木黄酮对LM细胞的增殖作用被废除。结论：ERα参与了通过与IGF-IR的早期关联，通过染料木黄酮与ERK/有丝分裂原活化蛋白激酶（MAPK）的瞬时激活，从而导致LM细胞的过度反应性，并确认ER信号通过ERK激活而增强ER信号传导。 /LM细胞中的MAPK。
BACKGROUND: Previously, we found that genistein at low concentrations stimulates the growth of human uterine leiomyoma (LM) cells, but not uterine smooth muscle (myometrial) cells (SMC). The aim of this study was to understand the molecular mechanism whereby genistein causes hyperproliferation of LM cells. METHODS: The effects of genistein at 1 mu g/ml on LM cells and SMC were evaluated using estrogen response element gene reporter, real-time RT-PCR, western blot, immunoprecipitation and cell proliferation assays. RESULTS: Elevated estrogen receptor (ER) transactivation, increased mRNA expression of early estrogen-responsive genes, progesterone receptor and insulin-like growth factor-I (IGF-I), and decreased protein levels of ER-alpha (ER alpha) were found in genistein-treated LM cells, but not SMC. Additionally, extracellular regulated kinase (ERK), Src homology/collagen (Shc) and ER alpha were transiently activated, and interactions between ER alpha and IGF-I receptor (IGF-IR) were rapidly induced by genistein in LM cells. Using ER antagonist ICI 182,780 and MAPK/ERK kinase (MEK) inhibitor PD98059, we found that these early events were inhibited and the proliferative effect of genistein on LM cells was abrogated. CONCLUSIONS: ER alpha is involved in the transient activation of ERK/mitogen activated protein kinase (MAPK) by genistein via its early association with IGF-IR, leading to hyper-responsiveness of LM cells and confirming that ER signaling is enhanced by activation of ERK/MAPK in LM cells.