Journal
VIROLOGY
Volume 485, Issue -, Pages 340-354Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2015.08.003
Keywords
Vesicular stomatitis virus; Oncolytic virus; Pancreatic cancer; Interferon signaling; NF-kappa B (NF-kappa B); Janus kinase (JAK); IKK inhibitor; TPCA-1; Ruxolitinib
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Funding
- NIH National Cancer Institute [1R15CA167517-01]
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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.
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