Naringenin suppresses growth of human placental choriocarcinoma via reactive oxygen species-mediated P38 and JNK MAPK pathways
Naringenin suppresses growth of human placental choriocarcinoma via reactive oxygen species-mediated P38 and JNK MAPK pathways
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DOI：
10.1016/j.phymed.2017.08.026
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发表时间：
2018-11-15
期刊：
影响因子：
7.9
通讯作者：
Song, Gwonhwa
中科院分区：
文献类型：
--
作者：
Park, Sunwoo;Lim, Whasun;Song, Gwonhwa
背景：胎盘绒毛膜癌是一种高转移率和复发率的妊娠滋养细胞肿瘤。然而，一些患者与绒毛膜癌是化疗耐药的常规chemotherapeutic agents.Hypothesis：柚皮素增加人胎盘绒毛膜癌cells.Methods：我们研究了柚皮素对人胎盘绒毛膜癌细胞增殖和迁移的影响，并进行TUNEL和Annexin V/PI染色检测柚皮素对这两种细胞的凋亡作用。此外，我们研究了线粒体膜电位（MMP）的损失和线粒体活性氧（ROS）的产生，以确定通过线粒体介导的绒毛膜癌细胞凋亡的具体原因。与柚皮素在绒毛膜癌细胞系中诱导产生ROS一致，我们研究了在NH 4和JEG 3细胞中的脂质过氧化和谷胱甘肽水平，因为两者都受到ROS的影响。我们接下来确定了剂量依赖性的影响，柚皮素及其药理学抑制剂的信号转导通路中，在MEDIAN和JEG 3细胞通过western blot analysis.Results：柚皮素降低的活力和迁移功能的两个细胞系，并增加线粒体相关的细胞凋亡诱导的ROS和脂质过氧化，降低谷胱甘肽和降低线粒体膜电位MMP在剂量依赖性的方式。我们还以剂量-反应方式测定了柚皮素激活的ERK 1/2、P38、JNK和P70 S6 K在JEG 3细胞中的磷酸化。虽然柚皮素诱导的AKT蛋白磷酸化在p53细胞，它抑制磷酸化的蛋白在JEG 3细胞。此外，我们还通过将柚皮素与PI 3 K和MAPK通路的药理学抑制剂以及ROS抑制剂联合应用于TNM和JEG 3细胞系，证实了柚皮素诱导细胞信号传导的机制。总的来说，研究结果表明，柚皮素是一种潜在的抗肿瘤治疗分子，通过诱导ROS的产生和MAPK途径的激活对绒毛膜癌细胞产生癌症效应。
Background: Human placental choriocarcinoma is a gestational trophoblastic tumor with high rates of metastasis and reoccurrence. However, some patients with choriocarcinoma are chemoresistance to conventional chemotherapeutic agents.Hypothesis: Naringenin increases apoptosis in human placental choriocarcinoma cells.Methods: We investigated the effects of naringenin on proliferation and migration of JAR and JEG3 cells, and performed TUNEL and Annexin V/PI staining assays to examine apoptotic effects of naringenin on both cells. In addition, we studied the loss of mitochondrial membrane potential (MMP) and the production of mitochondrial reactive oxygen species (ROS) to determine the specific reason for apoptosis of choriocarcinoma cells being mediated via mitochondria. Consistent with the induction of production of ROS by naringenin in both choriocarcinoma cell lines, we investigated lipid peroxidation and glutathione levels in both JAR and JEG3 cells since both are affected by ROS. We next determined dose-dependent effects of naringenin and its pharmacological inhibitors on signal transduction pathways in JAR and JEG3 cells by western blot analyses.Results: Naringenin reduced viability and migratory functions of both cell lines, and increased mitochondria related apoptosis induced by ROS and lipid peroxidation, decreased glutathione and decreased mitochondrial membrane potential MMP in a dose-dependent manner. We also determined naringenin activated phosphorylation of ERK1/2, P38, JNK and P70S6K in JAR and JEG3 cells in a dose-response manner. Although naringenin induced phosphorylation of AKT proteins in JAR cells, it suppressed phosphorylation of the protein in JEG3 cells. In addition, we confirmed the mechanism of naringenin-induced cell signaling by using a combination of naringenin and pharmacological inhibitors of the PI3K and MAPK pathways, as well as a ROS inhibitor in JAR and JEG3 cell lines.Conclusions: Collectively, results of this study indicate that naringenin is a potential therapeutic molecule with anti-cancer effects on choriocarcinoma cells by inducing generation of ROS and activation of the MAPK pathways.