IFN-γ upregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma
IFN-γ upregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma
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DOI：
10.1002/ijc.10516
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发表时间：
2002-08-01
影响因子：
6.4
通讯作者：
McDonald, JM
中科院分区：
文献类型：
--
作者：
Ahn, EY;Pan, G;McDonald, JM
胆管癌是一种目前尚无有效治疗方法且预后不良的恶性肿瘤。以前，我们证明了培养的人胆管癌细胞系在其表面上不均匀地表达Fas，导致2个亚群，Fas高和Fas低细胞。Fas-低细胞对Fas抗体和钙调蛋白拮抗剂他莫昔芬和三氟拉嗪诱导的细胞凋亡具有抗性，并且在裸鼠中是致瘤性的（Pan等人，Am J Pathol 1999; 155：193-203）。在这里，我们表明，IFN-γ增强Fas高和Fas低细胞的凋亡。IFN-γ在两种细胞系中上调许多凋亡相关分子，包括Fas、半胱天冬酶-3、半胱天冬酶-4、半胱天冬酶-7、半胱天冬酶-8和巴克。IFN-γ预处理促进Fas介导的caspase裂解、细胞色素c释放和Bax易位。在裸鼠中证实了IFN-γ抑制Fas-低细胞的肿瘤发生的能力。腔内注射IFN-γ使肿瘤体积减小78%。这些发现表明IFN-γ通过上调凋亡相关基因来调节凋亡途径。这使得致瘤性Fas低的胆管癌细胞非致瘤性和敏感的Fas凋亡，从而代表一种可能的治疗方式。(C)2002 Wiley-Liss，Inc.
Human cholangiocarcinoma is a malignancy with no effective therapy and a poor prognosis. Previously, we demonstrated that cultured human cholangiocarcinoma cell lines heterogeneously express Fas on their surface, resulting in 2 subpopulations, Fas-high and Fas-low cells. Fas-low cells are resistant to apoptosis induced by Fas antibody and the calmodulin antagonists tamoxifen and trifluoperazine and are tumorigenic in nude mice (Pan et al., Am J Pathol 1999; 155: 193-203). Here, we show that IFN-gamma enhances apoptosis in both Fas-high and Fas-low cells. IFN-gamma upregulates many apoptosis-related molecules, including Fas, caspase-3, caspase-4, caspase-7, caspase-8 and Bak, in both cell lines. Pretreatment with IFN-gamma facilitated Fas-mediated caspase cleavage, cytochrome c release and Bax translocation. The ability of IFN-gamma to inhibit tumorigenesis of Fas-low cells was demonstrated in nude mice. Intraturnoral injection of IFN-gamma decreased tumor volumes by 78%. These findings indicate that IFN-gamma modulates the apoptotic pathway by upregulating apoptosis-related genes. This renders tumorigenic Fas-low cholangiocarcinoma cells nontumorigenic and sensitive to Fas apoptosis, thus representing a possible therapeutic modality. (C) 2002 Wiley-Liss, Inc.