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

Virology
Marcela CataldiValery Z Grdzelishvili

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.

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Citations

Jan 31, 2017·Journal of Cellular Biochemistry·Safieh EbrahimiSeyed Mahdi Hassanian
Nov 17, 2017·The Journal of General Virology·Sébastien A Felt, Valery Z Grdzelishvili
Jan 26, 2018·Science Translational Medicine·Mohammed SelmanJean-Simon Diallo
Sep 28, 2016·World Journal of Gastroenterology : WJG·Fang HuangYi-Gang Wang
Aug 30, 2019·International Journal of Molecular Sciences·Kevin KojokYahye Merhi
Aug 29, 2018·ACS Infectious Diseases·Michael PhanJean-Simon Diallo

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