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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / immunology*
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Autophagy / drug effects
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Autophagy / genetics
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Autophagy / immunology*
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Autophagy-Related Protein 5
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Cell Line, Tumor
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Cells, Cultured
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DEAD-box RNA Helicases / metabolism
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Endosomes / drug effects
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Endosomes / genetics
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Endosomes / metabolism
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Humans
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Immunity, Innate*
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Interferon-Induced Helicase, IFIH1
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Lysosomes / drug effects
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Lysosomes / genetics
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Lysosomes / metabolism
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Melanoma / immunology*
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Melanoma / pathology
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Melanoma / therapy
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Mice
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Microtubule-Associated Proteins / metabolism
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Microtubule-Associated Proteins / physiology
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Phagosomes / drug effects
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Phagosomes / genetics
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Phagosomes / metabolism
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Poly C / pharmacology
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Polyethyleneimine / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Double-Stranded
Substances
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Antineoplastic Agents
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Atg5 protein, mouse
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Autophagy-Related Protein 5
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Map1lc3b protein, mouse
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Microtubule-Associated Proteins
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Pmaip1 protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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RNA, Double-Stranded
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Poly C
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Polyethyleneimine
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Ifih1 protein, mouse
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1