Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)
Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)
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DOI：
10.1016/j.taap.2014.05.008
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发表时间：
2014-08-15
影响因子：
3.8
通讯作者：
Wang, Fei
中科院分区：
文献类型：
--
作者：
Guo, Jiajia;Yuan, Yun;Wang, Fei
芳香酶是脊椎动物中唯一催化雌激素生物合成的酶。尽管芳香酶抑制剂已被开发用于治疗雌激素依赖性乳腺癌，但芳香酶的全身抑制会导致严重的副作用。因此，组织选择性芳香酶抑制剂对于治疗雌激素依赖性癌症很重要。在这项研究中，检测了 63 种不同结构的天然产物对人卵巢颗粒样 KGN 细胞雌激素生物合成的影响。两种化合物反式植醇 (SA-20) 和 (22E)-ergosta-6,9,22-triene-3 beta,5 alpha,8 alpha-triol (SA-48) -被发现有效抑制雌激素生物合成（IC50：分别为 1 muM 和 0.5 muM）。两种化合物均降低 KGN 细胞中芳香酶 mRNA 和蛋白表达水平，但对芳香酶过表达 HEK293A 细胞和重组表达芳香酶的芳香酶催化活性没有影响。这两种化合物降低了芳香酶启动子 I.3/II 的表达。这两种化合物都不影响细胞内环AMP (cAMP) 水平，但它们抑制cAMP 反应元件结合蛋白(CREB) 的磷酸化或蛋白表达。检查了这两种化合物对细胞外调节激酶 (ERK)、c-Jun N 末端激酶 (JNK)、p38 丝裂原激活蛋白激酶 (MAPK) 和 AKT/磷酸肌醇 3-激酶 (PI3K) 通路的影响。 p38 MAPK 的抑制可能是这些化合物作用的机制。我们的结果表明，结构与 SA-20 和 SA-48 相似的天然产物可能是组织选择性芳香酶调节剂的新来源，并且 p38 MAPK 在卵巢颗粒细胞芳香酶的基础控制中发挥重要作用。 SA-20 和 SA-48 作为预防和治疗雌激素依赖性癌症的新药物工具值得进一步研究。 (C) 2014 Elsevier Inc. 保留所有权利。
Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3 beta,5 alpha,8 alpha-triol (SA-48)-were found to potently inhibit estrogen biosynthesis (IC50: 1 mu M and 0.5 mu M, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. (C) 2014 Elsevier Inc. All rights reserved.