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首页> 外文期刊>Cell cycle >Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERα-positive breast cancer cells
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Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERα-positive breast cancer cells

机译：吲哚-3-甲醇及其N-烷氧基衍生物优先靶向ERα阳性乳腺癌细胞

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lndole-3-carbinol (l3C) is a natural anti-carcinogemc compound found at high concentrations in Brassica vegetables. I3C was recently reported to inhibit neutrophil elastase (NE) activity, while consequently limiting the proteolytic processing of full length cylin E into pro-tumorigenic low molecular weight cyclin E (LMW-E). In this study, we hypothesized that inhibition of NE activity and resultant LMW-E generation is critical to the anti-tumor effects of 13C. LMW-E was predominately expressed by ERα-negative breast cancer cell lines. However, ER α-positive cell lines demonstrated the greatest sensitivity to the anti-tumor effects of 13C, its more potent N-alkoxy denvatwes, We found that l3C was incapable of inhibiting NE ac:tivity or the generation of LMW-E. Therefore, this pathway did not: contribute to theanti-tumor activity of I3C, Gene expression analyzes idenufied ligand-activated aryl hydrocarbon receptor (AhR), which mediated sensitivity to the anti-tumor effects of 13C in ERa-positive MCF- cells. In this model system, the reactive oxygen species (ROS)-induced upregulation of ATE-, pro-apoptotic BH3-only proteins (e.g. NOXA) contributed to the sensitivity of ERa-positive breast cancer cells to the anti-tumor effects of l3C. Overexpression of ERα in MDA-MB -23 cells, which normally lack ERa expression, increased sensitivity to the anti-tumor elfects of l3C, demonstrating a drect role for ERa in mediating the sensitivity of breast cancer cell lines to BC. Our results suggest that ERa signaling amplified the pro -apoptotic effect of 13-C -signaling AhR signaling in luminal breast cancer cell lines, which was mediated in part through oxidative stress induced upregulation of ATF-3 and downstream BH3 -only proteins.
机译：吲哚-3-甲醇（lC）是在芸苔属蔬菜中发现的高浓度天然抗癌基因化合物。据报道，I3C抑制中性粒细胞弹性蛋白酶（NE）的活性，因此限制了全长cylin E的蛋白水解过程，成为促肿瘤的低分子量细胞周期蛋白E（LMW-E）。在这项研究中，我们假设抑制NE活动和由此产生的LMW-E生成对于13C的抗肿瘤作用至关重要。 LMW-E主要由ERα阴性乳腺癌细胞系表达。然而，ERα阳性细胞系对13C的抗肿瘤作用表现出最大的敏感性，其更有效的N-烷氧基牙本质。我们发现13C不能抑制NE活性或LMW-E的产生。因此，该途径没有：促进I3C的抗肿瘤活性，基因表达分析了识别的配体激活的芳基烃受体（AhR），后者介导了对Era阳性MCF细胞中13C的抗肿瘤作用的敏感性。在该模型系统中，活性氧（ROS）诱导的仅ATE促凋亡BH3蛋白（例如NOXA）上调有助于Era阳性乳腺癌细胞对13C的抗肿瘤作用的敏感性。正常情况下缺乏ERa表达的MDA-MB -23细胞中ERα的过表达增加了对13C抗肿瘤效应的敏感性，这表明ERa在介导乳腺癌细胞系对BC敏感性中起直接作用。我们的结果表明，ERα信号放大了13-C信号AhR信号在腔乳腺癌细胞系中的促凋亡作用，这部分是由氧化应激诱导的ATF-3和仅下游BH3蛋白的上调介导的。

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