Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of DR5
Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of DR5
复制标题
DOI：
10.1158/0008-5472.can-05-1568
复制
发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Choi, KS
中科院分区：
文献类型：
--
作者：
Kim, H;Kim, EH;Choi, KS
萝卜硫素是一种化学预防剂，存在于包括西兰花在内的各种十字花科蔬菜中。在这里，我们表明，与肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）与亚毒性剂量的莱菔硫烷的组合治疗显着诱导快速凋亡的TRAIL耐药肝癌细胞。无论是TNF-α，也不Fas介导的凋亡在肝癌细胞的cotentiation与萝卜硫素，表明萝卜硫素可以选择性地敏感细胞TRAIL诱导的凋亡，但不其他死亡受体介导的凋亡。我们发现萝卜硫素处理显著上调TRAIL死亡受体DR 5的mRNA和蛋白水平。这是伴随着活性氧（ROS）的产生增加。用N-乙酰-L-半胱氨酸预处理和过氧化氢酶过表达抑制萝卜硫素诱导的DR 5上调，几乎完全阻断了共处理诱导的细胞凋亡。此外，萝卜硫素介导的对TRAIL的致敏作用通过给予DR 5的阻断抗体或小干扰RNA而有效降低。这些结果共同表明，萝卜硫素诱导的ROS的产生和随后的DR 5的上调是触发和放大TRAIL诱导的凋亡信号传导的关键。我们还发现，萝卜硫素可以使Bcl-xL-和Bcl-2-过表达的肝癌细胞对TRAIL诱导的凋亡敏感，这表明用TRAIL和萝卜硫素的组合治疗可能是治疗耐药肝癌的安全策略。
Sulforaphane is a chemopreventive agent present in various cruciferous vegetables, including broccoli. Here, we show that treatment with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in combination with subtoxic doses of sulforaphane significantly induces rapid apoptosis in TRAIL-resistant hepatoma cells. Neither TNF-alpha- nor Fas-mediated apoptosis was sensitized in hepatoma cells by cotreatment with sulforaphane, suggesting that sulforaphane can selectively sensitize cells to TRAIL-induced apoptosis but not to apoptosis mediated by other death receptors. We found that sulforaphane treatment significantly up-regulated mRNA and protein levels of DR5, a death receptor of TRAIL. This was accompanied by an increase in the generation of reactive oxygen species (ROS). Pretreatment with N-acetyl-L-cysteine and overexpression of catalase inhibited sulforaphane-induced up-regulation of DR5 and almost completely blocked the cotreatment-induced apoptosis. Furthermore, the sulforaphane-mediated sensitization to TRAIL was efficiently reduced by administration of a blocking antibody or small interfering RNAs for DR5. These results collectively indicate that sulforaphane-induced generation of ROS and the subsequent up-regulation of DR5 are critical for triggering and amplifying TRAIL-induced apoptotic signaling. We also found that sulforaphane can sensitize both Bcl-xL- and Bcl-2-overexpressing hepatoma cells to TRAIL-induced apoptosis, indicating that treatment with a combination of TRAIL and sulforaphane may be a safe strategy for treating resistant hepatomas.