Genistein enhances TRAIL-induced apoptosis through inhibition of p38 MAPK signaling in human hepatocellular carcinoma Hep3B cells
Genistein enhances TRAIL-induced apoptosis through inhibition of p38 MAPK signaling in human hepatocellular carcinoma Hep3B cells
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DOI：
10.1016/j.cbi.2009.03.020
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发表时间：
2009-07-15
影响因子：
5.1
通讯作者：
Choi, Yung Hyun
中科院分区：
文献类型：
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作者：
Jin, Cheng-Yun;Park, Cheol;Choi, Yung Hyun
肿瘤坏死因子相关凋亡诱导配体（TRAIL）的细胞毒性作用在某些癌细胞中是有限的。然而，人们发现，治疗与TRAIL与无毒浓度的金雀异黄素敏化TRAIL耐药的人肝癌细胞Hep 3B细胞的TRAIL介导的凋亡。染料木黄酮和TRAIL联合处理诱导染色质浓缩和亚G1期DNA含量。这些凋亡指标与导致聚（ADP-核糖）聚合酶（PARP）裂解的半胱天冬酶活性诱导相关。caspase-3、-8和-9抑制剂均显著抑制联合处理诱导的细胞活力和PARP裂解，这表明caspase在观察到的细胞毒性效应中发挥重要作用。染料木黄酮治疗还引发了对p38-β丝裂原活化蛋白激酶（MAPK）活化的抑制。SB 203580预处理可显著增加TRAIL诱导的细胞凋亡中的亚G1期细胞数和线粒体膜电位（MMP）的丢失。与此相反，p38 MAPK的过表达保护细胞凋亡的共同处理与染料木素和TRAIL，这表明p38 MAPK作为细胞凋亡的关键调节剂，在人肝细胞癌Hep 3B细胞的治疗与染料木素和TRAIL的组合。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in some carcinoma cancer cells. However, it was found that treatment with TRAIL in combination with nontoxic concentrations of genistein sensitized TRAIL-resistant human hepatocellular carcinoma Hep3B cells to TRAIL-mediated apoptosis. Combined treatment with genistein and TRAIL-induced chromatin condensation and sub-G1 phase DNA content. These indicators of apoptosis were correlated with the induction of caspase activity that resulted in the cleavage of poly(ADP-ribose) polymerase (PARP). Both cell viability and the cleavage of PARP induced by combined treatment were significantly inhibited by caspase-3, -8 and -9 inhibitors, which demonstrates the important roles of caspases in the observed cytotoxic effects. Genistein treatment also triggered the inhibition of p38-beta mitogen-activated protein kinase (MAPK) activation. Pretreatment with SB203580 resulted in significantly increased sub-G1 population and loss of mitochondrial membrane potential (MMP) in TRAIL-induced apoptosis. By contrast, overexpression of p38 MAPK protected apoptosis by co-treatment with genistein and TRAIL, suggesting that the p38 MAPK act as key regulators of apoptosis in response to treatment with a combination of genistein and TRAIL in human hepatocellular carcinoma Hep3B cells. (C) 2009 Elsevier Ireland Ltd. All rights reserved.