Phytochemical-induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis and differentiation in malignant melanoma cells
Phytochemical-induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis and differentiation in malignant melanoma cells
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DOI：
10.1016/j.phymed.2017.12.006
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发表时间：
2018-01-15
期刊：
影响因子：
7.9
通讯作者：
Choi, Kyung-Chul
中科院分区：
文献类型：
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作者：
Heo, Jae-Rim;Lee, Geum-A;Choi, Kyung-Chul
背景：植物化学物质来源于植物、蔬菜和日常生活用品，具有化学预防作用。恶性黑色素瘤是高度转移性的，黑色素瘤患者可以对常规的melanoma therapy.Methods：在本研究中，我们研究了植物化学物质山奈酚（Kaem），染料木素（Gen）和3 '3-二吲哚甲烷（DIM）对黑色素瘤细胞活力的抗癌作用。我们还评估了细胞周期相关基因表达的改变。我们验证了生产的细胞内活性氧（ROS）和内质网（ER）的压力在蛋白质和细胞水平上使用蛋白质印迹，TUNEL法，和二氢二氯荧光素二乙酸酯（DCF-DA）assay.Results：处理A375 SM黑色素瘤细胞与植物化学物质导致细胞生长抑制。植物化学物质处理增加了p21基因的表达，降低了细胞周期蛋白E和/或细胞周期蛋白B的基因表达。这三种植物化学物质通过增加磷酸化p38 MAPK和p53的水平来激活ROS-p38-p53细胞凋亡途径，并通过增加磷酸化eIF 2 α和C/EBP同源蛋白（CHOP）的水平来激活ER应激介导的细胞凋亡途径。ROS-p38-p53和ER应激介导的途径均通过减弱Bcl-2表达和上调BAX来诱导线粒体凋亡途径。形态学变化的检测表明，Kaem和Gen可以诱导A375 SM细胞株分化。结论：这些结果表明，植物化学物质是潜在的有用的治疗黑色素瘤，由于其能够抑制黑色素瘤细胞的生长和分裂，通过ROS和ER应激途径。
Background: Phytochemicals are derived from plants, vegetables and daily products and exert chemopreventive effects. Malignant melanoma is highly metastatic, and melanoma patients can develop chemotherapeutic resistance against conventional melanoma therapies.Methods: In the present study, we investigated the anti-cancer effect of the phytochemicals kaempferol (Kaem), genistein (Gen), and 3'3-diindolylmethane (DIM) on melanoma cell viability. We also evaluated the altered expression of cell cycle-related genes. We verified the production of intracellular reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress at both the protein and cellular level using a western blot, TUNEL assay, and Dihydrodichlorofluorescein diacetate (DCF-DA) assay.Results: Treatment of A375SM melanoma cells with phytochemicals resulted in inhibition of cell growth. Treatment with phytochemicals increased the gene expression of p21 and decreased the gene expression of cyclin E and/or cyclin B. The three phytochemicals activated the ROS-p38-p53 apoptotic pathway by increasing the level of phosphorylated p38 MAPK and p53, and they activated the ER stress-mediated apoptotic pathway by increasing the level of phosphorylated eIF2 alpha and C/EBP homologous protein (CHOP). Both the ROS-p38-p53 and ER stress-mediated pathway induced the mitochondrial apoptotic pathway by attenuating Bcl-2 expression and upregulating BAX. Detection of morphological changes demonstrated that Kaem and Gen can induce differentiation in A375SM cell line.Conclusion: These results indicate that phytochemicals are potentially useful in treatments for melanoma due to their ability to inhibit melanoma cell growth and division via the ROS and ER stress pathway.