Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1
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...
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| Veröffentlicht in: | Virology (New York, N.Y.) N.Y.), 2015-11, Vol.485, p.340-354 |
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| creator | Cataldi, Marcela Shah, Nirav R Felt, Sébastien A Grdzelishvili, Valery Z |
| description | 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. |
| doi_str_mv | 10.1016/j.virol.2015.08.003 |
| format | Article |
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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.</description><identifier>ISSN: 0042-6822</identifier><identifier>EISSN: 1096-0341</identifier><identifier>DOI: 10.1016/j.virol.2015.08.003</identifier><identifier>PMID: 26331681</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amides - pharmacology ; Cell Line, Tumor ; Cytopathogenic Effect, Viral - drug effects ; Humans ; I-kappa B Kinase - antagonists & inhibitors ; IKK inhibitor ; Infectious Disease ; Interferon signaling ; Interferon Type I - metabolism ; Janus kinase (JAK) ; Janus Kinases - antagonists & inhibitors ; Janus Kinases - metabolism ; Myxovirus Resistance Proteins - genetics ; NF-kappa B (NF-κB) ; Oncolytic virus ; Oncolytic Viruses - drug effects ; Oncolytic Viruses - physiology ; Pancreatic cancer ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - virology ; Protein Kinase Inhibitors - pharmacology ; Pyrazoles - pharmacology ; Ruxolitinib ; Sendai virus - drug effects ; Sendai virus - physiology ; Signal Transduction - drug effects ; STAT Transcription Factors - metabolism ; Thiophenes - pharmacology ; TPCA-1 ; Vesicular stomatitis Indiana virus - drug effects ; Vesicular stomatitis Indiana virus - physiology ; Vesicular stomatitis virus ; Virus Replication - drug effects</subject><ispartof>Virology (New York, N.Y.), 2015-11, Vol.485, p.340-354</ispartof><rights>Elsevier Inc.</rights><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. 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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.</description><subject>Amides - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cytopathogenic Effect, Viral - drug effects</subject><subject>Humans</subject><subject>I-kappa B Kinase - antagonists & inhibitors</subject><subject>IKK inhibitor</subject><subject>Infectious Disease</subject><subject>Interferon signaling</subject><subject>Interferon Type I - metabolism</subject><subject>Janus kinase (JAK)</subject><subject>Janus Kinases - antagonists & inhibitors</subject><subject>Janus Kinases - metabolism</subject><subject>Myxovirus Resistance Proteins - genetics</subject><subject>NF-kappa B (NF-κB)</subject><subject>Oncolytic virus</subject><subject>Oncolytic Viruses - drug effects</subject><subject>Oncolytic Viruses - physiology</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - virology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrazoles - pharmacology</subject><subject>Ruxolitinib</subject><subject>Sendai virus - drug effects</subject><subject>Sendai virus - physiology</subject><subject>Signal Transduction - drug effects</subject><subject>STAT Transcription Factors - metabolism</subject><subject>Thiophenes - pharmacology</subject><subject>TPCA-1</subject><subject>Vesicular stomatitis Indiana virus - drug effects</subject><subject>Vesicular stomatitis Indiana virus - physiology</subject><subject>Vesicular stomatitis virus</subject><subject>Virus Replication - drug effects</subject><issn>0042-6822</issn><issn>1096-0341</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkttuEzEQhi0EoqHwBEjIl9xs8KydPVxQqUQcqlYCiXJtee3ZxOnGDrZ3pTwDL42XlAq44cqH-f-Z0XxDyEtgS2BQvdktJxv8sCwZrJasWTLGH5EFsLYqGBfwmCwYE2VRNWV5Rp7FuGP5XdfsKTkrK86hamBBfrwLqO6s29CA0caknEbqe3rIlxxJVlM9_wWqcRgiTZ4qR1VK6EaV0NAp2_Q4qEBj8vtsSDbS3NiYtdvgx82WKur8hANVOtnJpuOc_-r6mlq3tZ1NPtDbL-vLAp6TJ70aIr64P8_Jtw_vb9efipvPH6_WlzeFXoFIhQbDewMlspZ3fd2h6SujhepQt00jRAes432rG4216eumbQUzDHpQPOu54efk4pT3MHZ7NBpdCmqQh2D3KhylV1b-HXF2Kzd-kqKCFkqeE7y-TxD89xFjknsb5_koh36MEuqyFrwVgmUpP0l18DEG7B_KAJMzRrmTvzDKGaNkjcwYs-vVnx0-eH5zy4K3JwHmOU0Wg4zaYuZkbECdpPH2PwUu_vHrwTqr1XCHR4w7PwaXEUiQsZRMfp03aV4kWGW34A3_CYUZyO0</recordid><startdate>20151101</startdate><enddate>20151101</enddate><creator>Cataldi, Marcela</creator><creator>Shah, Nirav R</creator><creator>Felt, Sébastien A</creator><creator>Grdzelishvili, Valery Z</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20151101</creationdate><title>Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1</title><author>Cataldi, Marcela ; Shah, Nirav R ; Felt, Sébastien A ; Grdzelishvili, Valery Z</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c514t-c1d3fd12e093bf7bedf6dc4abec98844b10b3f9c8ce7df789940d01f1a33bf3d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amides - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cytopathogenic Effect, Viral - drug effects</topic><topic>Humans</topic><topic>I-kappa B Kinase - antagonists & inhibitors</topic><topic>IKK inhibitor</topic><topic>Infectious Disease</topic><topic>Interferon signaling</topic><topic>Interferon Type I - metabolism</topic><topic>Janus kinase (JAK)</topic><topic>Janus Kinases - antagonists & inhibitors</topic><topic>Janus Kinases - metabolism</topic><topic>Myxovirus Resistance Proteins - genetics</topic><topic>NF-kappa B (NF-κB)</topic><topic>Oncolytic virus</topic><topic>Oncolytic Viruses - drug effects</topic><topic>Oncolytic Viruses - physiology</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - virology</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrazoles - pharmacology</topic><topic>Ruxolitinib</topic><topic>Sendai virus - drug effects</topic><topic>Sendai virus - physiology</topic><topic>Signal Transduction - drug effects</topic><topic>STAT Transcription Factors - metabolism</topic><topic>Thiophenes - pharmacology</topic><topic>TPCA-1</topic><topic>Vesicular stomatitis Indiana virus - drug effects</topic><topic>Vesicular stomatitis Indiana virus - physiology</topic><topic>Vesicular stomatitis virus</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cataldi, Marcela</creatorcontrib><creatorcontrib>Shah, Nirav R</creatorcontrib><creatorcontrib>Felt, Sébastien A</creatorcontrib><creatorcontrib>Grdzelishvili, Valery Z</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Virology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cataldi, Marcela</au><au>Shah, Nirav R</au><au>Felt, Sébastien A</au><au>Grdzelishvili, Valery Z</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1</atitle><jtitle>Virology (New York, N.Y.)</jtitle><addtitle>Virology</addtitle><date>2015-11-01</date><risdate>2015</risdate><volume>485</volume><spage>340</spage><epage>354</epage><pages>340-354</pages><issn>0042-6822</issn><eissn>1096-0341</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26331681</pmid><doi>10.1016/j.virol.2015.08.003</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Virology (New York, N.Y.), 2015-11, Vol.485, p.340-354 |
| issn | 0042-6822 1096-0341 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4619123 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | Amides - pharmacology Cell Line, Tumor Cytopathogenic Effect, Viral - drug effects Humans I-kappa B Kinase - antagonists & inhibitors IKK inhibitor Infectious Disease Interferon signaling Interferon Type I - metabolism Janus kinase (JAK) Janus Kinases - antagonists & inhibitors Janus Kinases - metabolism Myxovirus Resistance Proteins - genetics NF-kappa B (NF-κB) Oncolytic virus Oncolytic Viruses - drug effects Oncolytic Viruses - physiology Pancreatic cancer Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - virology Protein Kinase Inhibitors - pharmacology Pyrazoles - pharmacology Ruxolitinib Sendai virus - drug effects Sendai virus - physiology Signal Transduction - drug effects STAT Transcription Factors - metabolism Thiophenes - pharmacology TPCA-1 Vesicular stomatitis Indiana virus - drug effects Vesicular stomatitis Indiana virus - physiology Vesicular stomatitis virus Virus Replication - drug effects |
| title | Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1 |
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