An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells.
An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells.
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DOI：
10.1016/j.virol.2015.04.017
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发表时间：
2015-09
期刊：
影响因子：
3.7
通讯作者：
Grdzelishvili VZ
中科院分区：
文献类型：
--
作者：
Hastie E;Cataldi M;Steuerwald N;Grdzelishvili VZ
病毒编码的肿瘤抑制基因p53转基因表达已成功地用于水泡性口炎病毒（VSV）和其他溶瘤病毒（OV），以增强其抗癌活性。然而，还已知p53通过增强的I型干扰素（IFN）抗病毒应答来抑制病毒复制。为了研究p53转基因是否增强人胰腺导管腺癌（PDAC）细胞中的抗病毒信号传导，我们设计了编码人p53或先前描述的嵌合p53-CC的新型VSV重组体，其包含来自断点簇区（BCR）蛋白的卷曲螺旋（CC）结构域，并避免了内源性表达的突变型p53的显性负活性。与预期的p53增强抗病毒信号传导相反，我们对PDAC细胞中基因表达的全球分析表明，p53和p53-CC均显著抑制I型IFN应答。我们的数据表明，这是通过p53介导的NF-κB通路的抑制而发生的。重要的是，VSV编码的p53或p53-CC不抑制非恶性人类胰腺导管细胞中的抗病毒信号传导，其保留对所有VSV重组体的抗性。据我们所知，这是p53介导的抗病毒信号抑制的第一份报告，它表明OV编码的p53可以同时产生抗癌活性，同时帮助，而不是抑制，癌细胞中的病毒复制。
Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retain their resistance to all VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells.