Authors:
Damià Tormo, Agnieszka Chęcińska, Direna Alonso-Curbelo, Eva Pérez-Guijarro, Estela Cañón, Erica Riveiro-Falkenbach, Tonantzin G. Calvo, Lionel Larribere, Diego Megías, Francisca Mulero, Miguel A. Piris, Rupesh Dash, Paola M. Barral, José L. Rodríguez-Peralto, Pablo Ortiz-Romero, Thomas Tüting, Paul B. Fisher, and María S. Soengas
Summary:
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.
Source:
Cancer Cell; Vol. 16, Issue 2, 103-114 (08/04/09)