| Literature DB >> 26331681 |
Marcela Cataldi1, Nirav R Shah1, Sébastien A Felt1, Valery Z Grdzelishvili2.
Abstract
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.Entities:
Keywords: IKK inhibitor; Interferon signaling; Janus kinase (JAK); NF-kappa B (NF-κB); Oncolytic virus; Pancreatic cancer; Ruxolitinib; TPCA-1; Vesicular stomatitis virus
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Year: 2015 PMID： 26331681 PMCID： PMC4619123 DOI： 10.1016/j.virol.2015.08.003
Source DB: PubMed Journal: Virology ISSN： 0042-6822 Impact factor: 3.616