Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells.
Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells.
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DOI：
10.1093/toxsci/70.2.193
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发表时间：
2002-12
期刊：
影响因子：
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通讯作者：
J. Vondráček;A. Kozubík;M. Machala
中科院分区：
文献类型：
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作者：
J. Vondráček;A. Kozubík;M. Machala
已有研究表明，多环芳烃的雌激素活性可能通过促进组织特异性细胞增殖来促进其致癌作用。已知苯并[a]芘(BaP)和苯并[a]菲(BAA)都能微弱激活雌激素受体(ER)依赖的报告结构。在这项研究中，其他几种多环芳烃，包括荧烯、荧菲、芘、大黄素、菲和菲，在稳定转染荧光素酶报告基因的MCF-7细胞系中被发现是非常弱的内质网介导活性的诱导剂。多环芳烃的作用是时间依赖的，它们不能被抗雌激素ICI182,780完全抑制。此外，BaP和BAA以及弱雌激素样荧蒽可显著增强17β-雌二醇的最大ER介导活性。因此，研究了几种已知能以非配体依赖的方式激活ERα的蛋白激酶抑制剂的作用。然而，在该模型中，细胞外信号调节激酶1和2(ERK1/2)、磷脂酰肌醇-3激酶、蛋白激酶C、c-Src或蛋白激酶A的抑制剂或诱导剂都不能改变ER介导的活性。雌二醇和BAA都不能激活ERK1/2，这两个激酶被认为在ER信号转导中发挥重要作用，这表明另一种激酶参与了观察到的ERα的磷酸化。与17β-雌二醇类似，BAA刺激MCF-7细胞发生G(0)/G(1)-S期转变，ICI182,780可完全抑制这种转变。综上所述，部分多环芳烃在体外可增强17β-雌二醇诱导的内质网激活，刺激细胞周期进入。然而，它们的确切作用模式(S)以及这一现象是否与体内相关仍有待阐明。
It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.