Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1.
Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1.
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DOI：
10.1016/j.virol.2015.08.003
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发表时间：
2015-11
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：
Cataldi M;Shah NR;Felt SA;Grdzelishvili VZ
水泡性口炎病毒(VSV)是一种对大多数人胰腺导管腺癌(PDAC)细胞株有效的溶瘤病毒。然而，一些PDAC细胞株对溶瘤VSV-ΔM51感染具有高度抵抗力。为了更好地了解病毒耐药的机制，我们测试了一组不同细胞信号通路的16种小分子抑制剂，并确定TPCA-1(IKK-β抑制剂)和Ruxolitinib(JAK1/2抑制剂)是所有Δ耐药细胞系中病毒复制和病毒介导的溶瘤的强有力的促进剂。TPCA-1和Ruxolitinib类似地抑制STAT1和STAT2的磷酸化，并减少抗病毒基因MxA和OAS的表达。此外，原位激酶测定提供了TPCA-1直接抑制JAK1激酶活性的生化证据。综上所述，我们的研究结果表明，TPCA-1是一种独特的IKK-β和JAK1激酶的双重抑制因子，并为上调的I型干扰素信号在胰腺癌细胞对溶瘤病毒的耐药性中发挥重要作用提供了新的证据。
Vesicular stomatitis virus (VSV) is an effective oncolytic virus against most human pancreatic ductal adenocarcinoma (PDAC) cell lines. However, some PDAC cell lines are highly resistant to oncolytic VSV-ΔM51 infection. To better understand the mechanism of resistance, we tested a panel of 16 small molecule inhibitors of different cellular signaling pathways, and identified TPCA-1 (IKK-β inhibitor) and ruxolitinib (JAK1/2 inhibitor), as strong enhancers of VSV-ΔM51 replication and virus-mediated oncolysis in all VSV-resistant PDAC cell lines. Both TPCA-1 and ruxolitinib similarly inhibited STAT1 and STAT2 phosphorylation and decreased expression of antiviral genes MxA and OAS. Moreover, an in situ kinase assay provided biochemical evidence that TPCA-1 directly inhibits JAK1 kinase activity. Together, our data demonstrate that TPCA-1 is a unique dual inhibitor of IKK-β and JAK1 kinase, and provide a new evidence that upregulated type I interferon signaling plays a major role in resistance of pancreatic cancer cells to oncolytic viruses.