Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells.
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.
Besch
Robert
R
Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany. robert.besch@med.uni-muenchen.de
Poeck
Hendrik
H
Hohenauer
Tobias
T
Senft
Daniela
D
Häcker
Georg
G
Berking
Carola
C
Hornung
Veit
V
Endres
Stefan
S
Ruzicka
Thomas
T
Rothenfusser
Simon
S
Hartmann
Gunther
G
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D053453:Caspase 9 / Q000502:physiology; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D000072640:Interferon-Induced Helicase, IFIH1; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology*; D011070:Poly I-C / Q000494:pharmacology; D011094:Polyethyleneimine / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051020:bcl-X Protein / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; D007370:Interferon Type I; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D011094:Polyethyleneimine; D053453:Caspase 9; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C