Wogonin and Related Natural Flavones Overcome Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Protein Resistance of Tumors by Down-regulation of c-FLIP Protein and Up-regulation of TRAIL Receptor 2 Expression
Wogonin and Related Natural Flavones Overcome Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Protein Resistance of Tumors by Down-regulation of c-FLIP Protein and Up-regulation of TRAIL Receptor 2 Expression
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DOI：
10.1074/jbc.m111.286526
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发表时间：
2012-01-02
影响因子：
4.8
通讯作者：
Li-Weber, Min
中科院分区：
文献类型：
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作者：
Ding, Jie;Polier, Gernot;Li-Weber, Min
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是一种很有前途的抗肿瘤药物，它能杀死多种肿瘤细胞而不损伤正常组织。然而，许多癌症仍然对TRAIL具有抗性。为了克服TRAIL抗性，使用TRAIL途径的敏化剂的组合疗法将是有效的方法。为了研究TRAIL诱导细胞凋亡的潜在致敏剂，我们使用TRAIL耐药的人T细胞白血病病毒1型（HTLV-1）相关成人T细胞白血病/淋巴瘤（ATL）细胞作为模型系统。到目前为止，HTLV-1相关的ATL无法通过目前已知的疗法治愈。在这里，我们表明，汉黄芩素和结构上相关的天然黄酮芹菜素和白杨素打破TRAIL耐药HTLV-1相关的ATL的转录下调c-FLIP，死亡受体信号传导的关键抑制剂，并通过上调TRAIL受体2（TRAIL-R2）。这种作用是通过p53拮抗剂鼠双微体2（Mdm 2）的转录抑制介导的，导致p53水平的增加，从而导致p53靶基因TRAIL-R2的上调。我们还表明，这些黄酮可以敏化TNF α和CD 95介导的细胞死亡。此外，我们还发现汉黄芩素、芹菜素和白杨素也通过相同的机制增强了其他人类癌细胞系中TRAIL介导的凋亡，包括乳腺癌细胞系MDA-MB-231、结肠癌细胞系HT-29、肝细胞癌细胞系HepG 2、黑色素瘤细胞系SK-MEL-37和胰腺癌细胞系Capan-1。因此，我们的研究表明，这些黄酮作为TRAIL介导的抗癌治疗的佐剂的潜在用途。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that kills various tumor cells without damaging normal tissues. However, many cancers remain resistant to TRAIL. To overcome TRAIL resistance, combination therapies using sensitizers of the TRAIL pathway would be an efficacious approach. To investigate potential sensitizers of TRAIL-induced apoptosis, we used TRAIL-resistant human T cell leukemia virus type 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL) cells as a model system. So far, HTLV-1-associated ATL is incurable by presently known therapies. Here, we show that wogonin and the structurally related natural flavones apigenin and chrysin break TRAIL resistance in HTLV-1-associated ATL by transcriptional down-regulation of c-FLIP, a key inhibitor of death receptor signaling, and by up-regulation of TRAIL receptor 2 (TRAIL-R2). This effect is mediated through transcriptional inhibition of the p53 antagonist murine double minute 2(Mdm2), leading to an increase in p53 levels and, consequently, to up-regulation of the p53 target gene TRAIL-R2. We also show that these flavones can sensitize to TNF alpha- and CD95-mediated cell death. Furthermore, we show that wogonin, apigenin, and chrysin also enhance TRAIL-mediated apoptosis in other human cancer cell lines including breast cancer cell line MDA-MB-231, colon cancer cell line HT-29, hepatocellular carcinoma cell line HepG2, melanoma cell line SK-MEL-37, and pancreatic carcinoma cell line Capan-1 by the same mechanism. Thus, our study suggests the potential use of these flavones as an adjuvant for TRAIL-mediated anticancer therapy.