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Cancer Cell. 2009 Aug 4;16(2):103-14. doi: 10.1016/j.ccr.2009.07.004.

Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells.

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  • 1Melanoma Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

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.

Comment in

PMID:
19647221
[PubMed - indexed for MEDLINE]
PMCID:
PMC2851205
Free PMC Article

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