5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma

• Published in: Nature medicine Vol. 14; no. 11; pp. 1256 - 1263
• Main Authors: Akira, Shizuo, Busch, Dirk, Bscheider, Michael, Meyers, Rachel, Kato, Hiroki, Tüting, Thomas, Gaffal, Evelyn, Anz, David, Renn, Marcel, Rothenfusser, Simon, Kirschnek, Susanne, Schwerd, Tobias, Prinz, Marco, Tormo, Damia, Hellmuth, Johannes, Kalinke, Ulrich, Landsberg, Jennifer, Neuenhahn, Michael, Hartmann, Gunther, Berking, Carola, Maihoefer, Cornelius, Hornung, Veit, Schmidt, Andreas, Morskaya, Svetlana Shulga, Kremmer, Elisabeth, Bourquin, Carole, Poeck, Hendrik, Endres, Stefan, Besch, Robert, Ruland, Jürgen, Häcker, Georg
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2008; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis - immunology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Cell Transplantation; Cellular biology; Control; DEAD Box Protein 58; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Disease Models, Animal; Enzyme Activation; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetic aspects; Health aspects; Humans; Immunity, Innate - immunology; Infectious Diseases; Melanoma; Melanoma - genetics; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Metabolic Diseases; Mice; Molecular Medicine; Neurosciences; Oncology; Pathology; Phosphates - metabolism; Plasticity; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2; Receptors, Immunologic; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA, Small Interfering - therapeutic use; Skin cancer; Tumors; Germany
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1887

siRNA is used to silence expression of a specific gene and, if modified by a triphosphate at the 5′ end, will also activate the helicase Rig-I, leading to interferon production. Poeck
et al
. now combine both of these activities in a single siRNA to kill melanoma cells by crippling a crucial tumor cell survival pathway and triggering an interferon-dependent antitumor immune response (
pages 1152–1153
).
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.