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Citations to this article

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells
Robert Besch, … , Simon Rothenfusser, Gunther Hartmann
Robert Besch, … , Simon Rothenfusser, Gunther Hartmann
Published July 20, 2009
Citation Information: J Clin Invest. 2009;119(8):2399-2411. https://doi.org/10.1172/JCI37155.
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Research Article Article has an altmetric score of 10

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

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Abstract

The retinoic acid–inducible gene I (RIG-I) and melanoma differentiation–associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs. Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-I– and MDA-5–initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-xL rescued nonmalignant, but not melanoma, cells from RIG-I– and MDA-5–mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-I and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-xL, results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis.

Authors

Robert Besch, Hendrik Poeck, Tobias Hohenauer, Daniela Senft, Georg Häcker, Carola Berking, Veit Hornung, Stefan Endres, Thomas Ruzicka, Simon Rothenfusser, Gunther Hartmann

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 Total
Citations: 7 18 13 21 17 19 16 13 11 13 20 21 13 9 15 9 3 238
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2012 (9)

Title and authors Publication Year
Type I IFN-mediated regulation of IL-1 production in inflammatory disorders
K Ludigs, V Parfenov, RA Pasquier, G Guarda
Cellular and Molecular Life Sciences 2012
The role of innate immune signals in antitumor immunity
M Jinushi
OncoImmunology 2012
Targeting pattern recognition receptors in cancer immunotherapy
N Goutagny, Y Estornes, U Hasan, S Lebecque, C Caux
Targeted Oncology 2012
Triggering of the dsRNA Sensors TLR3, MDA5, and RIG-I Induces CD55 Expression in Synovial Fibroblasts
ON Karpus, KM Heutinck, PJ Wijnker, PP Tak, J Hamann
PloS one 2012
The Molecular Effects of a Polymorphism in the 5′UTR of Solute Carrier Family 44, Member 5 that Is Associated with Birth Weight in Holsteins
M Sugimoto, T Watanabe, Y Sugimoto
PloS one 2012
Selective Induction of Cell Death in Melanoma Cell Lines through Targeting of Mcl-1 and A1
D Senft, C Berking, SA Graf, C Kammerbauer, T Ruzicka, R Besch
PloS one 2012
IκB Kinase ε-Dependent Phosphorylation and Degradation of X-Linked Inhibitor of Apoptosis Sensitizes Cells to Virus-Induced Apoptosis
P Nakhaei, Q Sun, M Solis, T Mesplede, E Bonneil, S Paz, R Lin, J Hiscott
Journal of virology 2012
Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1
S Chiba, M Baghdadi, H Akiba, H Yoshiyama, I Kinoshita, H Dosaka-Akita, Y Fujioka, Y Ohba, JV Gorman, JD Colgan, M Hirashima, T Uede, A Takaoka, H Yagita, M Jinushi
Nature Immunology 2012
Innate immune agonist, dsRNA, induces apoptosis in ovarian cancer cells and enhances the potency of cytotoxic chemotherapeutics
DN Van, CF Roberts, JD Marion, S Lépine, KB Harikumar, J Schreiter, CI Dumur, X Fang, S Spiegel, JK Bell
The FASEB Journal 2012

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