Involvement of PI3K/Akt, ERK and p38 signaling pathways in emodin-mediated extrinsic and intrinsic human hepatoblastoma cell apoptosis
Involvement of PI3K/Akt, ERK and p38 signaling pathways in emodin-mediated extrinsic and intrinsic human hepatoblastoma cell apoptosis
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DOI：
10.1016/j.fct.2016.03.013
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发表时间：
2016-06-01
影响因子：
4.3
通讯作者：
Liu, Xuebo
中科院分区：
文献类型：
--
作者：
Cui, Yuting;Lu, Peiran;Liu, Xuebo
1，3，8-三羟基-6-甲基蒽醌（大黄素）是一种天然蒽醌衍生物，具有潜在的化学预防作用，但其肝细胞毒性的分子机制尚不清楚。目前的研究表明，大黄素靶向HepG 2细胞没有细胞毒性的原代人肝细胞相比，大黄酚和大黄酸。大黄素的抗增殖作用与凋亡有关，表现为溴化乙锭信号增强，DAPI荧光增强，半胱氨酸天冬氨酸蛋白酶原3（procaspase-3）和聚腺苷二磷酸核糖聚合酶（poly（ADP-ribose）polymerase）断裂，Annexin V-FITC/PI双染定量结果。此外，大黄素提高Bax/Bcl-2的比例，引起线粒体膜电位的破坏，并促进细胞色素c流出到胞质溶胶，指示的功能，依赖于细胞凋亡信号。大黄素同时导致Fas、Fas-L、caspase-8和tBid的激活，这引起死亡受体凋亡信号。值得注意的是，激活的tBid将Fas凋亡信号传递到线粒体途径。大黄素还能有效抑制Akt和ERK的磷酸化，促进p38的磷酸化。通过调节线粒体途径和/或死亡受体途径抑制PI 3 K/Akt和ERK以及激活p38介导大黄素诱导的细胞凋亡。此外，在大黄素诱导的细胞凋亡中，PI 3 K/Akt和MAPK 5通路之间存在交叉作用。(C)2016爱思唯尔有限公司版权所有
As a natural anthraquinone derivative, 1,3,8-trihydroxy-6-methylanthraquinone, known as emodin, has recently been reported to possess potential chemopreventive capacity, but the underlying molecular mechanism of its hepatocyte toxicity remains poorly clarified. The present research indicated that emodin targeted HepG2 cells without being cytotoxic to primary human hepatocyte cells in comparison with chrysophanol and rhein. The anti-proliferative effect of emodin was ascribed to occurrence of apoptosis, which characterized by higher ethidium bromide signal, brighter DAPI fluorescence, cleavages of procaspase-3 and poly (ADP-ribose) polymerase as well as quantitative result from Annexin V-FITC/PI double staining. Furthermore, emodin improved Bax/Bcl-2 ratio, elicited disruption of mitochondrial membrane potential and promoted efflux of cytochrome c to cytosol, indicative of features of mitochondria-dependent apoptotic signals. Emodin concurrently led to activations of Fas, Fas-L, caspase-8 and tBid, which provoked death receptor apoptotic signals. Notably, activated tBid relayed the Fas apoptotic signal to the mitochondrial pathway. Besides, emodin effectively attenuated phosphorylations of Akt and ERK and promoted phosphorylation of p38. Inhibitions of PI3K/Akt and ERK and activation of p38 mediated emodin-induced apoptosis through modulating the mitochondrial pathway and/or death receptor pathway. Additionally, there was a cross-talk between PI3K/Akt and MAPK5 pathways in emodin-induced apoptosis. (C) 2016 Elsevier Ltd. All rights reserved.