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

Autophagy
Direna Alonso-Curbelo, María S Soengas

Abstract

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.

Citations

Oct 15, 2011·Pigment Cell & Melanoma Research·Agnieszka Checinska, María S Soengas
Jul 31, 2010·Journal of Biomedicine & Biotechnology·Bo JinAnthony E T Yeo
Jan 16, 2013·International Journal of Nanomedicine·Li ChenWeili Yan
Sep 25, 2012·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Chia-Wei LinYee-Shin Lin
May 3, 2019·Journal for Immunotherapy of Cancer·M Angela AznarIgnacio Melero
Nov 12, 2021·EMBO Molecular Medicine·David OlmedaMaría S Soengas

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