5'-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma.
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.
Poeck
Hendrik
H
Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
Besch
Robert
R
Maihoefer
Cornelius
C
Renn
Marcel
M
Tormo
Damia
D
Morskaya
Svetlana Shulga
SS
Kirschnek
Susanne
S
Gaffal
Evelyn
E
Landsberg
Jennifer
J
Hellmuth
Johannes
J
Schmidt
Andreas
A
Anz
David
D
Bscheider
Michael
M
Schwerd
Tobias
T
Berking
Carola
C
Bourquin
Carole
C
Kalinke
Ulrich
U
Kremmer
Elisabeth
E
Kato
Hiroki
H
Akira
Shizuo
S
Meyers
Rachel
R
Häcker
Georg
G
Neuenhahn
Michael
M
Busch
Dirk
D
Ruland
Jürgen
J
Rothenfusser
Simon
S
Prinz
Marco
M
Hornung
Veit
V
Endres
Stefan
S
Tüting
Thomas
T
Hartmann
Gunther
G
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
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