title: 5'-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma.
abstract: Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid-induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I-mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule-based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.
authors.affiliation: Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Poeck
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
authors.forename: Cornelius
authors.initials: C
authors.lastname: Maihoefer
authors.forename: Marcel
authors.initials: M
authors.lastname: Renn
authors.forename: Damia
authors.initials: D
authors.lastname: Tormo
authors.forename: Svetlana Shulga
authors.initials: SS
authors.lastname: Morskaya
authors.forename: Susanne
authors.initials: S
authors.lastname: Kirschnek
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Landsberg
authors.forename: Johannes
authors.initials: J
authors.lastname: Hellmuth
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmidt
authors.forename: David
authors.initials: D
authors.lastname: Anz
authors.forename: Michael
authors.initials: M
authors.lastname: Bscheider
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwerd
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
authors.forename: Carole
authors.initials: C
authors.lastname: Bourquin
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Rachel
authors.initials: R
authors.lastname: Meyers
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
authors.forename: Michael
authors.initials: M
authors.lastname: Neuenhahn
authors.forename: Dirk
authors.initials: D
authors.lastname: Busch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Simon
authors.initials: S
authors.lastname: Rothenfusser
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010710:Phosphates / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D011971:Receptors, Immunologic
chemical_list: D000970:Antineoplastic Agents; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C052617:Bcl2 protein, mouse; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases