Interferon-alpha sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-kappa B inactivation.
Interferon-alpha sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-kappa B inactivation.
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发表时间：
2003
期刊：
影响因子：
8
通讯作者：
Masaya Shigeno;K. Nakao;T. Ichikawa;Kasumi Suzuki;A. Kawakami;S. Abiru;Seiji Miyazoe;Y. Nakagawa;H. Ishikawa;K. Hamasaki;K. Nakata;N. Ishii;K. Eguchi
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作者：
Masaya Shigeno;K. Nakao;T. Ichikawa;Kasumi Suzuki;A. Kawakami;S. Abiru;Seiji Miyazoe;Y. Nakagawa;H. Ishikawa;K. Hamasaki;K. Nakata;N. Ishii;K. Eguchi
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是TNF超家族的一员，可诱导多种癌细胞凋亡，对正常细胞几乎没有影响。然而，人肝癌细胞对TRAIL诱导的凋亡具有抗性。由于干扰素-α（IFN-α）能够增强TNF-α诱导的某些癌细胞凋亡，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Hep 3B细胞凋亡，其中IFN-α上调TRAIL的死亡受体DR 5的表达，并下调具有抗凋亡功能的Survivin的表达。与此相反，IFN-α并不增强TRAIL诱导的HepG 2细胞凋亡，其中DR 5和生存素的表达不受IFN-α的影响。另一方面，在HuH-7和HepG 2细胞中，TRAIL激活由RelA-p50异源二聚体组成的NF-κ B，其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-κ B活化，并降低了其在HuH-7中的转录活性，但在HepG 2细胞中没有。此外，IFN-α预处理明显增强了HuH-7细胞中TRAIL介导的caspase-8活化。我们的研究结果表明，IFN-α可以敏感某些人肝癌细胞TRAIL诱导的凋亡，刺激其死亡信号和抑制这些细胞的生存功能。
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-kappa B 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.