Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation
Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation
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DOI：
10.1038/sj.onc.1206139
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发表时间：
2003-03-20
期刊：
影响因子：
8
通讯作者：
Eguchi, K
中科院分区：
文献类型：
--
作者：
Shigeno, M;Nako, K;Eguchi, K
肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL) 是 TNF 超家族的成员，可诱导多种癌细胞凋亡，而对正常细胞影响很小或没有影响。然而，人肝癌细胞对 TRAIL 诱导的细胞凋亡具有抵抗力。由于干扰素-α (IFN-α) 能够增强 TNF-α 诱导的某些癌细胞凋亡，因此我们评估了 IFN-α 对 TRAIL 诱导的人肝癌细胞凋亡的影响。 IFN-α预处理增强TRAIL诱导的HuH-7和Hep3B细胞凋亡，其中IFN-α上调TRAIL死亡受体DR5的表达，下调具有抗凋亡功能的survivin表达。相反，IFN-α不会增强TRAIL诱导的HepG2细胞凋亡，其中DR5和生存素的表达不受IFN-α的影响。另一方面，在HuH-7和HepG2细胞中，TRAIL激活由RelA-p50异二聚体组成的NF-kappaB，NF-kappaB是调节细胞存活的关键转录因子。然而，IFN-α 预处理抑制了 TRAIL 介导的 NF-κB 激活，并降低了 HuH-7 细胞中的转录活性，但在 HepG2 细胞中却没有。此外，IFN-α 预处理明显增强了 HuH-7 细胞中 TRAIL 介导的 caspase-8 激活。我们的结果表明，IFN-α 可以通过刺激其死亡信号传导并抑制这些细胞的生存功能，使某些人肝癌细胞对 TRAIL 诱导的细胞凋亡敏感。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Since interferon-alpha (IFN-alpha) is capable of enhancing TNF-alpha-induced apoptosis in certain cancer cells, we evaluated the effect of IFN-alpha on TRAIL-induced apoptosis of human hepatoma cells. IFN-alpha pretreatment enhanced TRAIL-induced apoptosis of HuH-7 and Hep3B cells, in which IFN-alpha upregulated the expression of DR5, a death receptor of TRAIL, and downregulated the expression of survivin, which has an antiapoptotic function. In contrast, IFN-alpha did not enhance TRAIL-induced apoptosis of HepG2 cells, in which expression of DR5 and survivin was not affected by IFN-alpha. On the other hand, TRAIL activated NF-kappaB composed of RelA-p50 heterodimer, a key transcription factor regulating cell survival, in HuH-7 and HepG2 cells. However, IFN-alpha pretreatment repressed the TRAIL-mediated activation of NF-kappaB and decreased its transcriptional activity in HuH-7 but not in HepG2 cells. Moreover, IFN-alpha pretreatment clearly augmented TRAIL-mediated caspase-8 activation in HuH-7 cells. Our results suggest that IFN-alpha could sensitize certain human hepatoma cells to TRAIL-induced apoptosis by stimulating its death signaling and by repressing the survival function in these cells.