Hastie Eric, Cataldi Marcela, Moerdyk-Schauwecker Megan J, Felt Sébastien A, Steuerwald Nury, Grdzelishvili Valery Z
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
Cannon Research Center, Carolinas Healthcare System, Charlotte, NC, USA.
Oncotarget. 2016 Sep 20;7(38):61601-61618. doi: 10.18632/oncotarget.11202.
Vesicular stomatitis virus (VSV) based recombinant viruses (such as VSV-ΔM51) are effective oncolytic viruses (OVs) against a majority of pancreatic ductal adenocarcinoma (PDAC) cell lines. However, some PDAC cell lines are highly resistant to VSV-ΔM51. We recently showed that treatment of VSV-resistant PDAC cells with ruxolitinib (JAK1/2 inhibitor) or TPCA-1 (IKK-β inhibitor) breaks their resistance to VSV-ΔM51. Here we compared the global effect of ruxolitinib or TPCA-1 treatment on cellular gene expression in PDAC cell lines highly resistant to VSV-ΔM51. Our study identified a distinct subset of 22 interferon-stimulated genes (ISGs) downregulated by both ruxolitinib and TPCA-1. Further RNA and protein analyses demonstrated that 4 of these genes (MX1, EPSTI1, XAF1, and GBP1) are constitutively co-expressed in VSV-resistant, but not in VSV-permissive PDACs, thus serving as potential biomarkers to predict OV therapy success. Moreover, shRNA-mediated knockdown of one of such ISG, MX1, showed a positive effect on VSV-ΔM51 replication in resistant PDAC cells, suggesting that at least some of the identified ISGs contribute to resistance of PDACs to VSV-ΔM51. As certain oncogene and tumor suppressor gene variants are often associated with increased tropism of OVs to cancer cells, we also analyzed genomic DNA in a set of PDAC cell lines for frequently occurring cancer associated mutations. While no clear correlation was found between such mutations and resistance of PDACs to VSV-ΔM51, the analysis generated valuable genotypic data for future studies.
基于水泡性口炎病毒（VSV）的重组病毒（如VSV-ΔM51）是针对大多数胰腺导管腺癌（PDAC）细胞系的有效溶瘤病毒（OV）。然而，一些PDAC细胞系对VSV-ΔM51具有高度抗性。我们最近发现，用鲁索替尼（JAK1/2抑制剂）或TPCA-1（IKK-β抑制剂）处理对VSV耐药的PDAC细胞可打破它们对VSV-ΔM51的抗性。在此，我们比较了鲁索替尼或TPCA-1处理对高度抵抗VSV-ΔM51的PDAC细胞系中细胞基因表达的整体影响。我们的研究鉴定出了一个由鲁索替尼和TPCA-1共同下调的22个干扰素刺激基因（ISG）的独特子集。进一步的RNA和蛋白质分析表明，这些基因中的4个（MX1、EPSTI1、XAF1和GBP1）在对VSV耐药的PDAC中组成性共表达，但在对VSV敏感的PDAC中不表达，因此可作为预测OV治疗成功的潜在生物标志物。此外，shRNA介导的对其中一个此类ISG（MX1）的敲低对耐药PDAC细胞中VSV-ΔM51的复制显示出积极作用，这表明至少一些鉴定出的ISG促成了PDAC对VSV-ΔM51的抗性。由于某些癌基因和肿瘤抑制基因变异通常与OV对癌细胞的嗜性增加相关，我们还分析了一组PDAC细胞系中的基因组DNA，以寻找常见的癌症相关突变。虽然未发现此类突变与PDAC对VSV-ΔM51的抗性之间存在明显相关性，但该分析为未来研究生成了有价值的基因型数据。
