Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1.
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.
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
Marcela
M
Cataldi
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
Nirav R
NR
Shah
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
Sébastien A
SA
Felt
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA. Electronic address: vzgrdzel@uncc.edu.
Valery Z
VZ
Grdzelishvili
D000577:Amides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007370:Interferon Type I / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D009570:Nitriles; D050504:Oncolytic Viruses / Q000187:drug effects / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000821:virology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D050791:STAT Transcription Factors / Q000378:metabolism; D029082:Sendai virus / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects
D000577:Amides; D007370:Interferon Type I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; D013876:Thiophenes; C540383:ruxolitinib; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; D053612:Janus Kinases; D051550:I-kappa B Kinase
IKK inhibitor; Interferon signaling; Janus kinase (JAK); NF-kappa B (NF-κB); Oncolytic virus; Pancreatic cancer; Ruxolitinib; TPCA-1; Vesicular stomatitis virus