Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer
Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer
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异甘草素通过下调花生四烯酸代谢网络和 PI3K/Akt 失活诱导人乳腺癌生长抑制和细胞凋亡
DOI：
10.1016/j.taap.2013.05.031
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发表时间：
2013-10-01
影响因子：
3.8
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Li, Ying;Zhao, Haixia;Yang, Jing
花生四烯酸（AA）衍生的类花生酸及其下游途径已被证明在乳腺癌的生长控制中起着至关重要的作用。在这里，我们证明异甘草素，黄酮类植物雌激素从甘草，诱导生长抑制和凋亡，通过下调AA代谢网络中的多个关键酶和PI 3 K/Akt在人乳腺癌中的失活。异甘草素降低MCF-7和MDA-MB-231细胞的细胞活力、5-溴-2 '-脱氧尿苷（BrdU）掺入和克隆形成能力，并诱导细胞凋亡，细胞质组蛋白相关DNA片段化分析、流式细胞术和Hoechst染色证实了这一点。此外，异甘草素抑制多种形式的AA代谢酶的mRNA表达，包括磷脂酶A2（PLA 2）、环氧合酶（考克斯）-2和细胞色素P450（CYP）4A，并减少其产物的分泌，包括前列腺素E-2（PGE（2））和20-羟基二十碳四烯酸（20-HETE），而不影响考克斯-1，5-脂氧合酶（5-LOX），5-脂氧合酶激活蛋白（FLAP）和白三烯B-4（LTB 4）。此外，它下调磷酸-PI 3 K、磷酸-PDK（Ser（241））、磷酸-Akt（Thr（308））、磷酸-Bad（Ser（136））和Bcl-x（L）表达的水平，从而激活半胱天冬酶级联并最终裂解聚（ADPribose）聚合酶（PARP）。相反，加入外源性类花生酸，包括PGE（2），LTB 4和20-HETE类似物（WIT 003），半胱天冬酶抑制剂，或组成型活性Akt的过表达逆转了异甘草素诱导的细胞凋亡。值得注意的是，异甘草素诱导裸鼠中MDA-MB-231人乳腺癌异种移植物的生长抑制和细胞凋亡，以及肿瘤内类花生酸和磷酸化Akt（Thr（308））水平的降低。总之，这些数据表明异甘草素通过下调AA代谢网络和PI 3 K/Akt失活诱导人乳腺癌的生长抑制和凋亡。(C)2013 Elsevier Inc. All rights reserved.
Arachidonic acid (AA)-derived eicosanoids and its downstream pathways have been demonstrated to play crucial roles in growth control of breast cancer. Here, we demonstrate that isoliquiritigenin, a flavonoid phytoestrogen from licorice, induces growth inhibition and apoptosis through downregulating multiple key enzymes in AA metabolic network and the deactivation of PI3K/Akt in human breast cancer. Isoliquiritigenin diminished cell viability, 5-bromo-2'-deoxyuridine (BrdU) incorporation, and clonogenic ability in both MCF-7 and MDA-MB-231cells, and induced apoptosis as evidenced by an analysis of cytoplasmic histone-associated DNA fragmentation, flow cytometry and hoechst staining. Furthermore, isoliquiritigenin inhibited mRNA expression of multiple forms of AA-metabolizing enzymes, including phospholipase A2 (PLA2), cyclooxygenases (COX)-2 and cytochrome P450 (CYP) 4A, and decreased secretion of their products, including prostaglandin E-2 (PGE(2)) and 20-hydroxyeicosatetraenoic acid (20-HETE), without affecting COX-1, 5-lipoxygenase (5-LOX), 5-lipoxygenase activating protein (FLAP), and leukotriene B-4 (LTB4). In addition, it downregulated the levels of phospho-PI3K, phospho-PDK (Ser(241)), phospho-Akt (Thr(308)), phospho-Bad (Ser(136)), and Bcl-x(L) expression, thereby activating caspase cascades and eventually cleaving poly(ADPribose) polymerase (PARP). Conversely, the addition of exogenous eicosanoids, including PGE(2), LTB4 and a 20-HETE analog (WIT003), and caspase inhibitors, or overexpression of constitutively active Akt reversed isoliquiritigenin-induced apoptosis. Notably, isoliquiritigenin induced growth inhibition and apoptosis of MDA-MB-231 human breast cancer xenografts in nude mice, together with decreased intratumoral levels of eicosanoids and phospho-Akt (Thr(308)). Collectively, these data suggest that isoliquiritigenin induces growth inhibition and apoptosis through downregulating AA metabolic network and the deactivation of PI3K/Akt in human breast cancer. (C) 2013 Elsevier Inc. All rights reserved.