Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-γ
Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-γ
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DOI：
10.4049/jimmunol.170.12.6329
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发表时间：
2003-06-15
影响因子：
4.4
通讯作者：
Abrams, SI
中科院分区：
文献类型：
--
作者：
Liu, KB;Abrams, SI
干扰素-γ被认为是调节抗肿瘤反应所必需的。然而，恶性细胞对IFN-γ的反应程度可能对抗肿瘤反应的总体疗效有深远影响。在这项研究中，我们研究了IFN-γ对Fas介导的凋亡的人原发性和转移性结肠癌细胞差异致敏的分子基础。为此，我们分析了IFN-γ诱导的基因表达的基因组规模，随后与IFN-γ和Fas介导的信号转导相关的特定基因的表达和功能的分析。我们发现，虽然两种细胞群体在基因组规模上对IFN-γ的反应表现出相似的基因表达谱，但IFN-γ调节基因的表达强度在原发性肿瘤中要大得多。值得注意的是，两个基因，一个参与IFN-γ介导的信号传导，IFN共有序列结合蛋白（ICSBP），一个参与Fas介导的信号传导，caspase-1，清楚地显示出差异诱导两个细胞系之间。在原发性肿瘤细胞中，ICSBP和caspase-1的表达强烈诱导IFN-γ的反应，而他们在转移性肿瘤细胞中弱至不可检测。功能研究表明，caspase-1和ICSBP参与Fas介导的细胞凋亡后IFN-γ敏化，但通过两个不同的途径进行。这项研究还首次报道了ICSBP在非造血肿瘤中的表达，表现出促凋亡特性。总之，在人结肠癌细胞模型中，我们确定了两个IFN-γ调节基因ICSBP和caspase-1在Fas介导的死亡机制中的重要功能贡献。
Interferon-gamma is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN-gamma may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN-gamma differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN-gamma-induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-gamma- and Fas-mediated signaling. We found that although both cell populations exhibited a similar gene expression profile at the genome scale in response to IFN-gamma, the expression intensities of the IFN-gamma-regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN-gamma-mediated signaling, IFN consensus sequence-binding protein (ICSBP), and one involved in Fas-mediated signaling, caspase-1, were clearly shown to be differentially induced between the two cell lines. In the primary tumor cells, the expression of ICSBP and caspase-1 was strongly induced in response to IFN-gamma; whereas they were weakly to nondetectable in the metastatic tumor cells. Functional studies demonstrated that both caspase-1 and ICSBP were involved in Fas-mediated apoptosis following IFN-gamma sensitization, but proceeded via two distinct pathways. This study also reports for the first time the expression of ICSBP in a nonhemopoietic tumor exhibiting proapoptotic properties. Overall, in a human colon carcinoma cell model, we identified important functional contributions of two IFN-gamma-regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death.