Journal
CANCER CELL
Volume 16, Issue 2, Pages 103-114Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2009.07.004
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Funding
- NIH [R01 CA107237]
- Spanish Ministry of Science and Innovation [SAF2008-1950, R01 GM068448, Tu90-6/1, DKH 10741]
- Asociacion Espahola Contra el Cancer
- Spanish National Cancer Research Centre
- Thelma Newmeyer Corman Chair in Cancer Research
- Spanish Ministry of Science and Innovation
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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.
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