Jin Cheng-Yun, Park Cheol, Moon Sung-Kwon, Kim Gi-Young, Kwon Taeg Kyu, Lee Su Jae, Kim Wun-Jae, Choi Yung Hyun
Department of Biomaterial Control (BK21 program), Dongeui University Graduate School, South Korea.
Anticancer Drugs. 2009 Sep;20(8):713-22. doi: 10.1097/CAD.0b013e32832e8998.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子超家族的一员，并且已经表明许多人类癌细胞系对TRAIL诱导的细胞死亡具有抗性。然而，抗性背后的分子机制尚不清楚。在本研究中，我们表明，大豆制品中发现的异黄酮染料木黄酮可逆转人肝癌细胞对TRAIL的抗性。染料木黄酮加TRAIL处理的细胞中协同诱导凋亡与促凋亡的仅含BH3结构域蛋白Bid的裂解有关。Bid表达的沉默减少了线粒体膜电位的降低，并减少了用染料木黄酮和TRAIL处理的细胞中的凋亡，证实Bid裂解是该反应所必需的。用半胱天冬酶-3和半胱天冬酶-8抑制剂预处理可减少联合处理诱导的凋亡。然而，单独用TRAIL处理诱导的半胱天冬酶-8活性与TRAIL加染料木黄酮处理并无差异；两者均有效诱导Bid裂解。这些数据表明，染料木黄酮消除了对TRAIL的Bid裂解的抗性，并且染料木黄酮不干扰肝癌细胞中Bid上游的信号。
