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Autophagic Punctum

Self-killing of melanoma cells by cytosolic delivery of dsRNA: Wiring innate immunity for a coordinated mobilization of endosomes, autophagosomes and the apoptotic machinery in tumor cells

Direna Alonso-Curbelo and María S. Soengas

Patients with metastatic melanoma have a poor prognosis, primarily due to a generalized inefficacy of current anticancer treatments. Therefore, the identification of novel death inducers with good bioavailability and safety profiles is a main priority in this disease. Here we summarize recent work from our group uncovering an unexpected ability of the dsRNA mimic polyinosine-polycytidylic acid (pIC) to engage the endo/lysosomal machinery of melanoma cells and induce their self degradation by autophagy and apoptosis, without noticeable secondary effects in vivo. However the anti-melanoma activity of pIC strictly required conjugation with carriers (e.g., polyethyleneimine, PEI) for cytosolic delivery. Combining transcriptome analyses with RNA interference, we found RNA helicase MDA-5 as a main driver of the pIC-PEI complex. MDA-5 in turn, favored NOXA-dependent activation of apoptotic caspases. These results demonstrate new therapeutically tractable links between autophagy and apoptosis that can be coordinately engaged in tumor cells by dsRNA mimics.

Addendum to: Tormo D, 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. Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell 2009; 16:103-14; PMID: 19647221; DOI: 10.1016/j.ccr.2009.07.004.

Authors

Direna Alonso-Curbelo

Spanish National Cancer Research Centre; Madrid, Spain

María S. Soengas Corresponding author: msoengas@cnio.es

Spanish National Cancer Research Centre; Madrid, Spain