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首页> 外文期刊>Molecular and Cellular Biology >Direct Repression of FLIP Expression by c-myc Is a Major Determinant of TRAIL Sensitivity
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Direct Repression of FLIP Expression by c-myc Is a Major Determinant of TRAIL Sensitivity

机译：c-myc直接抑制FLIP表达是TRAIL敏感性的主要决定因素

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Tumor necrosis factor alpha (TNF-α)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-α family of death receptor ligands and holds great therapeutic potential as a tumor cell-specific cytotoxic agent. Using a panel of established tumor cell lines and normal cells, we found a significant difference between the number of TRAIL-sensitive cells expressing high levels of c-myc and TRAIL-resistant cells expressing low levels of c-myc (P < 0.05, n = 19). We also found a direct linear correlation between c-myc levels and TRAIL sensitivity in TRAIL-sensitive cell lines (r = 0.94, n = 6). Overexpression of c-myc or activation of a myc-estrogen receptor (ER) fusion sensitized TRAIL-resistant cells to TRAIL. Conversely, small interfering RNA (siRNA)-mediated knockdown of c-myc significantly reduced both c-myc expression and TRAIL-induced apoptosis. The gene encoding the inhibitor of caspase activation, FLICE inhibitory protein (FLIP), appears to be a direct target of c-myc-mediated transcriptional repression. Overexpression of c-myc or activation of myc-estrogen receptor (ER) decreased FLIP levels both in cell culture and in mouse models of c-myc-induced tumorigenesis, while knocking down c-myc using siRNA increased FLIP expression. Chromatin immunoprecipitation and luciferase reporter analyses showed that c-myc binds and represses the human FLIP promoter. c-myc expression enhanced TRAIL-induced caspase 8 cleavage and FLIP cleavage at the death-inducing signaling complex. Combined siRNA-mediated knockdown of FLIP and c-myc resensitized cells to TRAIL. Therefore, c-myc down-regulation of FLIP expression provides a universal mechanism to explain the ability of c-myc to sensitize cells to death receptor stimuli. In addition, identification of c-myc as a major determinant of TRAIL sensitivity provides a potentially important screening tool for identification of TRAIL-sensitive tumors.
机译：肿瘤坏死因子α（TNF-α）相关凋亡诱导配体（TRAIL）是死亡受体配体的TNF-α家族成员，具有作为肿瘤细胞特异性细胞毒剂的巨大治疗潜力。使用一组已建立的肿瘤细胞系和正常细胞，我们发现表达高水平c-myc的TRAIL敏感细胞与表达低水平c-myc的TRAIL耐药细胞的数量之间存在显着差异（ P < / em> <0.05， n = 19）。我们还发现TRAIL敏感细胞系（ r = 0.94， n = 6）中c-myc水平与TRAIL敏感性之间存在直接线性关系。 c-myc的过表达或myc-雌激素受体（ER）融合的激活使TRAIL耐药细胞对TRAIL敏感。相反，小干扰RNA（siRNA）介导的c- myc 的敲低显着降低c-myc表达和TRAIL诱导的细胞凋亡。编码caspase激活抑制剂FLICE抑制蛋白（ FLIP ）的基因似乎是c-myc介导的转录抑制的直接靶标。 c-myc的过度表达或myc-雌激素受体（ER）的激活在细胞培养和c-myc诱导的肿瘤发生的小鼠模型中均降低了FLIP水平，而使用siRNA降低c- myc FLIP表达式。染色质的免疫沉淀和荧光素酶报告基因分析表明c-myc结合并抑制人类 FLIP 启动子。 c-myc表达增强了TRAIL诱导的caspase 8裂解和FLIP裂解，诱导了死亡。 siRNA介导的 FLIP 和c- myc 重敏细胞对TRAIL的组合。因此，FLIP表达的c-myc下调提供了一种普遍的机制来解释c-myc使细胞对死亡受体刺激敏感的能力。另外，鉴定c-myc作为TRAIL敏感性的主要决定因素为鉴定TRAIL敏感性肿瘤提供了潜在重要的筛选工具。

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