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.
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 antimelanoma 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.
Alonso-Curbelo
Direna
D
Melanoma Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Institute (CNIO), Madrid, Spain.
Soengas
María S
MS
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D003600:Cytosol / Q000378:metabolism / Q000473:pathology; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008954:Models, Biological; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000235:genetics / Q000502:physiology*
D012330:RNA, Double-Stranded