IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression
IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression
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DOI：
10.1158/0008-5472.can-04-4316
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Schreiber, RD
中科院分区：
文献类型：
--
作者：
Dunn, GP;Sheehan, KCF;Schreiber, RD
我们之前报道过 23% 的人肺腺癌细胞系对 IFN-γ 无反应。为了将这一发现扩展到来自不同来源组织的癌细胞，我们评估了 LNCaP 人前列腺癌细胞系中的 IFN-γ 受体信号传导，在其他人之前的实验中，该细胞系未能诱导一系列 IFN 依赖性生物反应。在本报告中，我们表明 LNCaP 细胞无法对 IFN-γ 或 IFN-α 做出反应，因为 IFN-γ 和 IFN-α/β 受体下游的近端信号事件受损，导致 STAT1 激活。此外，我们发现 LNCaP 对 IFN 不敏感是由于 JAK1 激酶表达缺失的结果，JAK1 激酶是 IFN-γ 和 IFN-α/β 受体共有的专性成分。在 LNCaP 细胞中，在蛋白质和信息水平上均检测不到 JAK1。用 DNA 甲基转移酶抑制剂和历史脱乙酰酶的组合处理 LNCaP 细胞可诱导 JAK1 信息的表达。这些结果确定了 LNCaP 细胞系中 IFN 不敏感的分子基础，并表明关键免疫信号成分的表观遗传沉默可能是肿瘤细胞逃避免疫检测和消除的一种机制。
We reported previously that 23% of human lung adenocarcinoma cell lines were unresponsive to IFN-gamma. To extend this finding to cancer cells derived from distinct tissues of origin, we assessed IFN-gamma receptor signaling in the LNCaP human prostate adenocarcinoma cell line, which in previous experiments by others failed to induce a range of IFN-dependent biological responses. In this report, we show that LNCaP cells fail to respond to either IFN-gamma or IFN-alpha because of an impairment in the proximal signaling events downstream of both IFN-gamma and IFN-alpha/beta receptors that lead to the activation of STAT1. Furthermore, we show that LNCaP insensitivity to the IFNs is a result of the absence of expression of the JAK1 kinase, an obligate component shared by both IFN-gamma and IFN-alpha/beta receptors. JAK1 was undetectable in LNCaP cells at both protein and message levels. Treatment of LNCaP cells with a combination of inhibitors of DNA methyltransferases and historic deacetylases induced expression of JAK1 message. These results identify the molecular basis for IFN insensitivity in the LNCaP cell line and suggest that epigenetic silencing of key immunologic signaling components may be one mechanism by which tumor cells evade immune detection and elimination.