Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells

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• 作者：Damià ; Tormo ; Agnieszka Chę ; ciń ; ska ; Direna Alonso-Curbelo ; Eva Pé ; rez-Guijarro ; Estela Cañ ; ó ; n ; Erica Riveiro-Falkenbach ; Tonantzin G. Calvo ; Lionel Larribere ; Diego Megí ; as ; Francisca Mulero ; Miguel A. Piris ; Rupesh Dash ; Paola M. Barral ; José ; L. Rodrí ; guez-P
• 刊名：Cancer Cell
• 出版年：2009
• 出版时间：4 August 2009
• 年：2009
• 卷：16
• 期：2
• 页码：103-114
• 全文大小：2483 K

文摘

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.