Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells.
Cancer Cell, 2009/8/04;16(2):103-14.
Tormo D[1], Checińska A, Alonso-Curbelo D, Pérez-Guijarro E, Cañón E, Riveiro-Falkenbach E, Calvo TG, Larribere L, Megías D, Mulero F, Piris MA, Dash R, Barral PM, Rodríguez-Peralto JL, Ortiz-Romero P, Tüting T, Fisher PB, Soengas MS
Affiliations
PMID: 19647221DOI: 10.1016/j.ccr.2009.07.004
Impact factor: 38.585
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.
MeSH terms
Animals; Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Protein 5; Cell Line, Tumor; Cells, Cultured; DEAD-box RNA Helicases; Endosomes; Humans; Immunity, Innate; Interferon-Induced Helicase, IFIH1; Lysosomes; Melanoma; Mice; Microtubule-Associated Proteins; Phagosomes; Poly C; Polyethyleneimine; Proto-Oncogene Proteins c-bcl-2; RNA, Double-Stranded
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