Interferon-a sensitizes human hepatoma cells to TRAIL-iduced apoptosis through DRS upregulation and NF-κB inactivation

干扰素-a 通过 DRS 上调和 NF-κB 失活使人肝癌细胞对 TRAIL 诱导的细胞凋亡敏感

• 批准号: 14570482
• 负责人: ISHII Nobuko
• 金额: $ 2.11万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570482/
• 关键词: TRAIL; interferon-α; hepatoma; survivin; NF-κB

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-a (IFN-α) is capable of enhancing TNF-a-induced apoptosis in certain cancer cells, we evaluated the effect of IFN-α on TRAIL-induced apoptosis of human hepatoma cells. IFN-α pretreatment enhanced TRAIL-induced apoptosis of HuH-7 and Hep3B cells, in which IFN-α upregulated the expression of DRS, a death receptor of TRAIL, and downregulated the expression of survivin, which has an anti-apoptotic function. In contrast, IFN-α did not enhance TRAIL-induced apoptosis of HepG2 cells, in which expression of DRS and survivin was not affected by IFN-α. On the other hand, TRAIL activated NF-κB composed of Re1A-p50 heterodimer, a key transcription factor regulating cell survival, in HuH-7 and HepG2 cells : However, IFN-α pretreatment repressed the TRAIL-mediated activation of NF-κB and decreased its transcriptional activity in HuH-7 but not in HepG2 cells. Moreover, IFN-α pretreatment clearly augmented TRAIL-mediated caspase-8 activation in HuH-7 cells. Our results suggest that IFN-α could sensitize eertain human hepatoma cells to TRAIL-induced apoptosis by stimulating its death signaling and by repressing the survival function in these cells.

肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是肿瘤坏死因子超家族的一员，它能诱导多种肿瘤细胞发生凋亡，而对正常细胞几乎没有作用。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能够增强肿瘤坏死因子-α诱导的某些肿瘤细胞的凋亡，我们评价了干扰素-α对TRAIL诱导人肝癌细胞凋亡的影响。干扰素-α可增强TRAIL诱导的HH-7和Hep3B细胞的凋亡，其中干扰素-α上调TRAIL死亡受体DRs的表达，下调具有抗凋亡作用的Survivin的表达。相反，干扰素-α不能增强TRAIL诱导的肝癌细胞的凋亡，而且干扰素-α不影响DRs和Survivin的表达。另一方面，TRAIL在HH-7和HEPG2细胞中激活了由调节细胞存活的关键转录因子Re1a-p50异源二聚体组成的NF-κB：但α-α预处理抑制了TRAIL介导的NF-κB的激活，并降低了其在HH-7细胞中的转录活性，但在HepG2细胞中则没有。此外，干扰素-α预处理可明显增强TRAIL介导的HH-7细胞中caspase-8的激活。我们的结果提示，干扰素-α可以通过刺激TRAIL诱导的某些人肝癌细胞的死亡信号和抑制这些细胞的生存功能而使其对TRAIL诱导的某些肝癌细胞的凋亡敏感。

项目成果

Masaya Shigeno, et al.: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. 22(11). 1653-1662 (2003)

Masaya Shigeno 等人：“干扰素-α 通过 DR5 上调和 NF-κB 失活使人肝癌细胞对 TRAIL 诱导的细胞凋亡敏感”Oncogene 22(11)。

Akira Saeki, Kazuhiko Nakao, Yuji Nagayama, Kenji Yanagi, Kojirou Matsumoto, Toshinobu Hayashi, Hiroki Ishikawa, Keisuke Hamasaki, Nobuko Ishii, Katsumi Eguchi.: "Diverse efficacy of vaccination therapy using the α-fetoprotein gene against mouse hepatocel

Akira Saeki、Kazuhiko Nakao、Yuji Nagayama、Kenji Yanagi、Kojirou Matsumoto、Toshinobu Hayashi、Hiroki Ishikawa、Keisuke Hamasaki、Nobuko Ishii、Katsumi Eguchi。：“使用甲胎蛋白基因针对小鼠肝细胞进行疫苗接种治疗的多种功效

Kenji Yanagi, et al.: "Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo."Int J Oncol.. 22(2). 345-351 (2003)

Kenji Yanagi 等人：“用表达 fms 样酪氨酸激酶 3 配体和 CD40 配体的腺病毒对体内小鼠肝癌细胞进行免疫基因治疗。”Int J Oncol.. 22(2)。

Masaya Shigeno, et al.: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. (in press). (2003)

Masaya Shigeno 等人：“干扰素-α 通过 DR5 上调和 NF-κB 失活使人肝癌细胞对 TRAIL 诱导的细胞凋亡敏感”Oncogene（出版中）。

Akira Saeki, et al.: "Diverse efficacy of vaccination therapy using the α-fetoprotein gene against mouse hepatocellular carcinoma."Int J Mol Med.. 13(1). 111-116 (2004)

Akira Saeki 等人：“使用甲胎蛋白基因针对小鼠肝细胞癌进行疫苗接种治疗的多种功效。”Int J Mol Med.. 13(1) (2004)。