Article abstract

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

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.

  1. Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
  2. Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilians University, Ziemssenstrasse 1, 80336 Munich, Germany.
  3. III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 15, 81675 Munich, Germany.
  4. Department of Dermatology and Allergology, Ludwig-Maximilians-University, Thalkirchner Strasse 48, 80337 Munich, Germany.
  5. Laboratory for Experimental Dermatology, Department of Dermatology and Allergology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
  6. Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, USA.
  7. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstrasse 30, 81675 Munich, Germany.
  8. Division of Immunology, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.
  9. Institute of Molecular Immunology, Helmholtz Zentrum München, Marchioninistrasse 25, 81377 Munich, Germany.
  10. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  11. Department of Neuropathology, University of Freiburg, Breisacherstrasse 64, 79106 Freiburg, Germany.
  12. These authors contributed equally to this work.

Correspondence to: Thomas Tüting5 e-mail:

Correspondence to: Gunther Hartmann1 e-mail:


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