Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1

被引：52

作者：

Cataldi, Marcela ^{[1
]}

Shah, Nirav R. ^{[1
]}

Felt, Sebastien A. ^{[1
]}

Grdzelishvili, Valery Z. ^{[1
]}

机构：

[1] Univ N Carolina, Dept Biol Sci, Charlotte, NC 28223 USA

来源：

VIROLOGY | 2015年 / 485卷

关键词：

Vesicular stomatitis virus; Oncolytic virus; Pancreatic cancer; Interferon signaling; NF-kappa B (NF-kappa B); Janus kinase (JAK); IKK inhibitor; TPCA-1; Ruxolitinib; NF-KAPPA-B; RECOMBINANT SENDAI-VIRUS; TUMOR-SPECIFIC DEFECTS; GENE-EXPRESSION; MYELOPROLIFERATIVE NEOPLASMS; DUCTAL ADENOCARCINOMA; ONCOLYTIC ACTIVITY; ANTIVIRAL ACTION; MATRIX PROTEIN; INTERFERON;

D O I：

10.1016/j.virol.2015.08.003

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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-Delta M51 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-beta inhibitor) and ruxolitinib (JAK1/2 inhibitor), as strong enhancers of VSV-Delta M51 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-beta 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. (C) 2015 Elsevier Inc. All rights reserved.

引用

页码：340 / 354

页数：15

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