Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion.
Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion.
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DOI：
10.1016/j.taap.2014.07.018
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发表时间：
2014-10
影响因子：
3.8
通讯作者：
Hao Zheng;Y. Li;Yuzhong Wang;Hai-lei Zhao;Jing Zhang;Hongyan Chai;T. Tang;J. Yue;Austin M Guo;Jing Yang
中科院分区：
文献类型：
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作者：
Hao Zheng;Y. Li;Yuzhong Wang;Hai-lei Zhao;Jing Zhang;Hongyan Chai;T. Tang;J. Yue;Austin M Guo;Jing Yang
黄酮类化合物具有广泛的体外抗侵袭和体内抗转移活性。失巢耐药发生在转移级联的多个关键阶段。在这里，我们证明了异甘草素(isiquiritigenin，ISL)，一种来自光面甘草的黄酮类化合物，通过下调环氧合酶(COX)-2和细胞色素P450(CYP)4A信号通路，抑制人乳腺癌的转移。流式细胞术和caspase裂解检测证实ISL可诱导人乳腺癌细胞MDA-MB-231和BT-549发生失巢凋亡。此外，ISL还能抑制体外培养的MDA-MB-231细胞磷脂酶A2、COX-2和CyP4A的表达，减少前列腺素E2(PGE2)和20-羟基二十碳四烯酸(20-HETE)的分泌。此外，它还能降低磷酸化PI3K(Tyr458)、磷酸化PDK(Ser241)和磷酸化Akt(Thr308)的水平。相反，外源添加PGE2、WIT003(20-HETE类似物)和EP4激动剂(CAY10580)或过表达组成活性Akt可逆转ISL诱导的失巢凋亡。ISL在体外具有抗迁移和抗侵袭活性，而PGE2、WIT003和CAY10580或过量表达固有活性Akt则逆转了ISL在MDA-MB-231细胞中的体外抗迁移和抗侵袭活性。值得注意的是，ISL抑制了MDA-MB-231细胞的体内转移，并降低了瘤内PGE2，20-HETE和磷酸化Akt的水平(Thr308)。综上所述，ISL通过下调COX-2和CYP4A信号通路，阻止失巢细胞抵抗、迁移和侵袭，从而抑制乳腺癌的转移。提示ISL可能成为预防乳腺癌转移的多靶点药物，失巢凋亡可能是黄酮类化合物发挥抗转移活性的一种新机制。
Flavonoids exert extensivein vitroanti-invasive andin vivoanti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E2(PGE2) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr458), phospho-PDK (Ser241) and phospho-Akt (Thr308). Conversely, the exogenous addition of PGE2, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted thein vitroanti-migratory and anti-invasive activities, whereas the addition of PGE2, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed thein vitroanti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited thein vivolung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE2, 20-HETE and phospho-Akt (Thr308). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasionviadownregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities.