Down-regulation of c-FLIP contributes to the sensitization effect of 3,3'-diindolylmethane on TRAIL-induced apoptosis in cancer cells.
Down-regulation of c-FLIP contributes to the sensitization effect of 3,3'-diindolylmethane on TRAIL-induced apoptosis in cancer cells.
复制标题
c-FLIP 的下调有助于 3,3-二吲哚基甲烷对 TRAIL 诱导的癌细胞凋亡的敏化作用。
DOI：
10.1158/1535-7163.mct-05-0249
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发表时间：
2005
影响因子：
5.7
通讯作者：
Ong,ChoonNam
中科院分区：
文献类型：
--
作者：
Zhang,Siyuan;Shen,Han-Ming;Ong,ChoonNam
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成员之一，可优先诱导肿瘤细胞凋亡，对正常细胞无不良影响。然而，仍有一些肿瘤细胞，特别是恶性程度较高的肿瘤细胞，对TRAIL诱导的凋亡产生抵抗，阻碍了TRAIL的临床抗癌功效。在本报告中，我们发现3，3 ′-二吲哚基甲烷，一种来自十字花科蔬菜的吲哚化合物，能够通过敏化TRAIL诱导的人癌细胞凋亡来克服TRAIL抗性。非细胞毒性浓度的3，3 ′-二吲哚甲烷通过促进caspase级联反应显著增强了TRAIL抗性癌细胞对TRAIL诱导的凋亡的抵抗力，这是一个独立于核因子-κB活化和细胞表面TRAIL受体表达的过程。在探索3，3 ′-二吲哚甲烷致敏活性的分子机制时，我们发现3，3 ′-二吲哚甲烷和TRAIL联合处理导致细胞FLICE抑制蛋白（c-FLIP）表达显著下调。此外，我们提供的证据表明，降低c-FLIP水平主要是介导的泛素-蛋白酶体降解系统。这些发现揭示了3，3 ′-二吲哚基甲烷的一种新的抗癌特性，并表明该化合物可能在癌症治疗中具有克服TRAIL耐药性的潜在用途。[Mol癌症治疗2005;4（12）：1972-81]
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, which has been shown to preferentially induce apoptosis in cancer cells without adverse effects on normal cells. However, there are still some cancer cells, especially those with high malignancy, resistant to TRAIL-induced apoptosis, impeding the clinical anticancer efficiency of TRAIL. In this report, we showed that 3,3′-diindolylmethane, an indole compound derived from cruciferous vegetables, is capable of overcoming TRAIL resistance by sensitizing TRAIL-induced apoptosis in human cancer cells. Noncytotoxic concentrations of 3,3′-diindolylmethane significantly enhanced TRAIL-resistant cancer cells to TRAIL-induced apoptosis via promoting the caspase cascade, a process independent of nuclear factor-κB activation and cell surface TRAIL receptor expression. In the search of the molecular mechanisms involved in the sensitization activity of 3,3′-diindolylmethane, we found that combined treatment of 3,3′-diindolylmethane and TRAIL led to significant down-regulation of the cellular FLICE inhibitory protein expression (c-FLIP). Furthermore, we provided evidence showing that the reduced c-FLIP level is predominately mediated by the ubiquitin-proteasome degradation system. These findings reveal a novel anticancer property of 3,3′-diindolylmethane and suggest that this compound could have potential use in cancer therapy to overcome TRAIL resistance. [Mol Cancer Ther 2005;4(12):1972–81]