Genistein sensitizes human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by enhancing Bid cleavage
Genistein sensitizes human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by enhancing Bid cleavage
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DOI：
10.1097/cad.0b013e32832e8998
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发表时间：
2009-09-01
影响因子：
2.3
通讯作者：
Choi, Yung Hyun
中科院分区：
文献类型：
--
作者：
Jin, Cheng-Yun;Park, Cheol;Choi, Yung Hyun
肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）是肿瘤坏死因子超家族的一员，研究表明，许多人类癌细胞系对TRAIL诱导的细胞死亡是不耐受的。然而，耐药的分子机制尚不清楚。在这项研究中，我们发现染料木素（一种在豆制品中发现的异黄酮）可以逆转人肝癌细胞对TRAIL的耐药性。染料木素加TRAIL处理的细胞协同诱导凋亡与Bid的裂解有关，Bid是一种促凋亡的BH3-only蛋白。在染料木黄酮和TRAIL处理的细胞中，沉默Bid表达减少了线粒体膜电位的下降和细胞凋亡的减少，证实了Bid切割是反应所必需的。用caspase-3和caspase-8抑制剂预处理可减少共处理诱导的细胞凋亡。然而，TRAIL单独处理诱导caspase-8活性与TRAIL加染料木黄酮没有差异；两者都有效地诱导了竞价解理。这些数据表明染料木素可以消除TRAIL对Bid切割的抗性，并且染料木素不会干扰肝癌细胞中Bid上游的信号。抗癌药物20:13 -722 (C) 2009 Wolters Kluwer Health bbb . Lippincott Williams & Wilkins。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and it has been shown that many human cancer cell lines are refractory to TRAIL-induced cell death. However, the molecular mechanisms underlying resistance are unclear. In this study, we show that TRAIL resistance is reversed in human hepatoma cells by genistein, an isoflavone found in soy products. Synergistic induction of apoptosis in cells treated with genistein plus TRAIL was associated with cleavage of Bid, a proapoptotic BH3-only protein. Silencing of Bid expression reduced decreases in mitochondrial membrane potential and reduced apoptosis in cells treated with genistein and TRAIL, confirming that Bid cleavage is required for the response. Pretreatment with caspase-3 and caspase-8 inhibitors reduced cotreatment-induced apoptosis. However, treatment with TRAIL alone induced caspase-8 activity that was not different than TRAIL plus genistein; both effectively induced Bid cleavage. These data suggest that genistein abolishes resistance to the Bid cleavage of TRAIL, and that genistein does not interfere with signals upstream of Bid in hepatoma cells. Anti-Cancer Drugs 20:713-722 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.