title: Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells.
abstract: 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.
authors: Melanoma Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Damià
authors: D
authors: Tormo
authors: Agnieszka
authors: A
authors: Checińska
authors: Direna
authors: D
authors: Alonso-Curbelo
authors: Eva
authors: E
authors: Pérez-Guijarro
authors: Estela
authors: E
authors: Cañón
authors: Erica
authors: E
authors: Riveiro-Falkenbach
authors: Tonantzin G
authors: TG
authors: Calvo
authors: Lionel
authors: L
authors: Larribere
authors: Diego
authors: D
authors: Megías
authors: Francisca
authors: F
authors: Mulero
authors: Miguel A
authors: MA
authors: Piris
authors: Rupesh
authors: R
authors: Dash
authors: Paola M
authors: PM
authors: Barral
authors: José L
authors: JL
authors: Rodríguez-Peralto
authors: Pablo
authors: P
authors: Ortiz-Romero
authors: Thomas
authors: T
authors: Tüting
authors: Paul B
authors: PB
authors: Fisher
authors: María S
authors: MS
authors: Soengas
mesh_terms: 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
chemical_list: 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