Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells.
Inappropriate drug delivery, secondary toxicities, and persistent chemo- and immunoresistance have traditionally compromised treatment response in melanoma. Using cellular systems and genetically engineered mouse models, we show that melanoma cells retain an innate ability to recognize cytosolic double-stranded RNA (dsRNA) and mount persistent stress response programs able to block tumor growth, even in highly immunosuppressed backgrounds. The dsRNA mimic polyinosine-polycytidylic acid, coadministered with polyethyleneimine as carrier, was identified as an unanticipated inducer of autophagy downstream of an exacerbated endosomal maturation program. A concurrent activity of the dsRNA helicase MDA-5 driving the proapoptotic protein NOXA resulted in an efficient autodigestion of melanoma cells. These results reveal tractable links for therapeutic intervention among dsRNA helicases, endo/lysosomes, and apoptotic factors.
Tormo
Damià
D
Melanoma Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Checińska
Agnieszka
A
Alonso-Curbelo
Direna
D
Pérez-Guijarro
Eva
E
Cañón
Estela
E
Riveiro-Falkenbach
Erica
E
Calvo
Tonantzin G
TG
Larribere
Lionel
L
Megías
Diego
D
Mulero
Francisca
F
Piris
Miguel A
MA
Dash
Rupesh
R
Barral
Paola M
PM
Rodríguez-Peralto
José L
JL
Ortiz-Romero
Pablo
P
Tüting
Thomas
T
Fisher
Paul B
PB
Soengas
María S
MS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1; D008247:Lysosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism / Q000502:physiology; D010588:Phagosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011066:Poly C / Q000494:pharmacology; D011094:Polyethyleneimine / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012330:RNA, Double-Stranded
D000970:Antineoplastic Agents; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012330:RNA, Double-Stranded; D011066:Poly C; D011094:Polyethyleneimine; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1