Access
To read this story in full you will need to login or make a payment (see right).
Article
Nature Medicine 14, 1256 - 1263 (2007)
Published online: 2 November 2008 | doi:10.1038/nm.1887
5'-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma
Hendrik Poeck1,2,3,12, Robert Besch4,12, Cornelius Maihoefer2,3,12, Marcel Renn5,12, Damia Tormo5, Svetlana Shulga Morskaya6, Susanne Kirschnek7, Evelyn Gaffal5, Jennifer Landsberg5, Johannes Hellmuth1, Andreas Schmidt2, David Anz2, Michael Bscheider2,3, Tobias Schwerd2, Carola Berking4, Carole Bourquin2, Ulrich Kalinke8, Elisabeth Kremmer9, Hiroki Kato10, Shizuo Akira10, Rachel Meyers6, Georg Häcker7, Michael Neuenhahn7, Dirk Busch7, Jürgen Ruland3, Simon Rothenfusser2, Marco Prinz11, Veit Hornung1, Stefan Endres2, Thomas Tüting5 & Gunther Hartmann1
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.
To read this story in full you will need to login or make a payment (see right).
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Il2 transcription unleashed by active DNA demethylationNature Immunology News and Views (01 Mar 2003)
RIG-ing an antitumor responseNature Medicine News and Views (01 Nov 2008)
See all 6 matches for News And ViewsRESEARCH
In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responsesNature Biotechnology Research (01 Oct 2009)
Drug Delivery?mediated Control of RNA ImmunostimulationMolecular Therapy Original Article
See all 36 matches for Research