Human Malignant Mesothelioma Cell Growth: Activation of Janus Kinase 2 and Signal Transducer and Activator of Transcription 1α for Inhibition by Interferon-γ
Human Malignant Mesothelioma Cell Growth: Activation of Janus Kinase 2 and Signal Transducer and Activator of Transcription 1α for Inhibition by Interferon-γ
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人恶性间皮瘤细胞生长：激活 Janus 激酶 2 和信号转导器以及转录激活剂 1α 以抑制干扰素-γ
DOI：
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
M. Jaurand
中科院分区：
文献类型：
--
作者：
A. Buard;C. Vivo;I. Monnet;C. Boutin;Y. Pilatte;M. Jaurand
胸膜内注射重组人 IFN-γ 在减少弥漫性恶性间皮瘤 (DMM) 早期阶段的肿瘤生长方面显示出一定的功效。在这里，我们通过研究七种人间皮瘤细胞系（HMCL）中 JAK/STAT 信号通路的激活，探讨了 IFN-γ 在 DMM 中的潜在治疗作用，这些细胞系对 IFN-γ 的抗增殖活性有不同的反应。我们发现，在 IFN-γ（500 单位/ml）抑制增殖的所有 HMCL 中，Janus 激酶 2 (JAK2) 和信号转导子和转录激活子 1 (STAT1) 在 15 分钟内在酪氨酸残基上被磷酸化。此外，在电泳迁移率变动分析中，15 分钟内检测到 STAT1 与 γ 激活位点 DNA 序列的结合活性，6 小时内在反应性较高的细胞中观察到 IFN 调节因子 1 RNA 表达（处理 72 小时后 DNA 合成抑制 72.7-95.2%）。相反，在一些 HMCL 中，缺乏或有限的生长抑制作用（DNA 合成抑制小于 22%）与 JAK2 或 STAT1 表达或激活的改变有关，或者与下游 IFN-γ 治疗后 IFN 调节因子 1 RNA 表达和/或 STAT1 蛋白表达的低诱导有关。这些数据表明，至少部分 IFN-γ 对 HMCL 增殖的影响是通过激活 JAK/STAT1 信号通路直接介导的，并且它可以解释在接受 IFN-γ 治疗的 DMM 患者中报告的抗肿瘤活性。
Intrapleural injections of recombinant human IFN-gamma have shown some efficacy in reducing tumor growth in early stages of diffuse malignant mesothelioma (DMM). Here, we have addressed the potential therapeutic effect of IFN-gamma in DMM by investigating the activation of the JAK/STAT signaling pathway in seven human mesothelioma cell lines (HMCLs) that were differentially responsive to the antiproliferative activity of IFN-gamma. We showed that janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) were phosphorylated on tyrosine residues within 15 min in all the HMCLs in which IFN-gamma (500 units/ml) inhibited proliferation. In addition, STAT1 binding activity to the gamma-activated sites DNA sequence was detected within 15 min in electrophoretic mobility-shift assay analysis, and IFN regulatory factor-1 RNA expression was observed within 6 h in the more responsive cells (72.7-95.2% inhibition of DNA synthesis after 72 h of treatment). Conversely, in several HMCLs, absent or limited growth suppressive effect (less than 22% inhibition of DNA synthesis) was associated with alterations in expression or activation of JAK2 or STAT1 or, downstream, with low induction of IFN regulatory factor-1 RNA expression and/or STAT1 protein expression following IFN-gamma treatment. These data suggest that at least part of the IFN-gamma effect on proliferation of HMCLs is mediated directly through activation of the JAK/STAT1 signaling pathway, and it could account for the antitumoral activity reported in DMM patients treated with IFN-gamma.
DOI：
10.1073/pnas.93.15.7673
发表时间：
1996-07-23
影响因子：
11.1
作者：
Bromberg, JF;Horvath, CM;Darnell, JE
通讯作者：
Darnell, JE