title: IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type I interferons-dependent and -independent anticancer activity.
abstract: RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of type I interferons (IFN) and pro-inflammatory cytokines through a sole adaptor IFN-β promoter stimulator-1 (IPS-1) (also known as Cardif, MAVS and VISA) in antiviral innate immunity. These sensors also have a pivotal role in anticancer activity through induction of apoptosis. However, the mechanism for their anticancer activity is poorly understood. Here, we show that anticancer vaccine adjuvant, PolyIC (primarily sensed by MDA5) and the oncolytic virus, Newcastle disease virus (NDV) (sensed by RIG-I), induce anticancer activity. The ectopic expression of IPS-1 into type I IFN-responsive and non-responsive cancer cells induces anticancer activity. PolyIC transfection and NDV infection upregulate pro-apoptotic gene TRAIL and downregulate the anti-apoptotic genes BCL2, BIRC3 and PRKCE. Furthermore, stable knockdown of IPS-1, IRF3 or IRF7 in IFN-non-responsive cancer cells show reduced anticancer activity by suppressing apoptosis via TRAIL and anti-apoptotic genes. Collectively, our study shows that IPS-1 induces anticancer activity through upregulation of pro-apoptotic gene TRAIL and downregulation of the anti-apoptotic genes BCL2, BIRC3 and PRKCE via IRF3 and IRF7 in type I IFN-dependent and -independent manners.
authors.affiliation: Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: H
authors.initials: H
authors.lastname: Ingle
authors.affiliation: Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: S
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: R S
authors.initials: RS
authors.lastname: Mahla
authors.affiliation: Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.affiliation: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takaoka
authors.affiliation: Pathogenomics Laboratory, ICAR-National Institute of High Security Animal Diseases, OIE Reference lab for Avian Influenza, Bhopal, India.
authors.forename: A A
authors.initials: AA
authors.lastname: Raut
authors.affiliation: 1] Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India [2] Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kumar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis / Q000276:immunology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D050839:Interferon Regulatory Factor-7 / Q000235:genetics; D007370:Interferon Type I / Q000276:immunology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000276:immunology*; D009522:Newcastle disease virus / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology; D051744:Protein Kinase C-epsilon / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000595707:BCL2 protein, human; D019496:Cancer Vaccines; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C505371:MAVS protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C497255:PRKCE protein, human; D051744:Protein Kinase C-epsilon; D011070:Poly I-C