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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
This study was supported by grant Biofuture 0311896 of the Bundesministerium für Bildung und Forschung and by grants SFB 704, SFB 670, KFO115 and KFO177 of the Deutsche Forschungsgemeinschaft to G. Hartmann; by grants Tu90-6/1 of the Deutsche Forschungsgemeinschaft and 10741 of the Deutsche Krebshilfe to T.T.; by grant 107805 of the Deutsche Krebshilfe to R.B.; by Graduiertenkolleg 1202 to C.M., M.B. and T.S.; by LMUexcellent (CIPSM 114, research professorship), and by SFB-TR 36 and En 169/7-2 of the Deutsche Forschungsgemeinschaft to S.E. and C. Bourquin. This work is part of the theses of C.M. and M.B. at the University of Munich and of M.R. and J.L. at the University of Bonn. We thank A. Dann for excellent technical assistance, T. Maniatis (Harvard University) and J. Chen (University of Texas Southwestern Medical Center) for providing IFN-β–Luc reporter plasmids and wild-type pPME-myc NS3-4A (NS3-4A), respectively, T. Fujita Institute for Virus Research, Kyoto University for providing Rig-I and the empty control vector and C. Borner (Institute of Molecular Medicine and Cell Research, University of Freiburg) for providing wild-type mouse Bcl-2 (mBcl-2/pcDNA).
Supplementary Tables 1–3, Supplementary Figs. 1–10 and Supplementary Methods
About this article
Direct RIG-I activation in human NK cells induces TRAIL-dependent cytotoxicity toward autologous melanoma cells
International Journal of Cancer (2019)