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

Volume 6, Issue 1   January 1, 2010
Pages 148 - 150
http://dx.doi.org/10.4161/auto.6.1.10464
Authors: Direna Alonso-Curbelo and María S. Soengas

View affiliations

Preview



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 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.

Autophagic Punctum to:
D Tormo, A Checińska, D Alonso-Curbelo, E Pérez-Guijarro, E Cañón, E Riveiro-Falkenbach, TG Calvo, L Larribere, D Megías, F Mulero, MA Piris, R Dash, PM Barral, JL Rodríguez-Peralto, P Ortiz-Romero, T Tüting, PB Fisher, MS Soengas. 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.2009.0

Advertisements