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PMID: 19647221 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells.

Cancer cell ·Vol. 16 ·No. 2 ·2009-08-04 ·Pages 103-14

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

Abstract

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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Apoptosis/drug effects,genetics,immunology Autophagy/drug effects,genetics,immunology Autophagy-Related Protein 5 Cell Line, Tumor Cells, Cultured DEAD-box RNA Helicases/metabolism Endosomes/drug effects,genetics,metabolism Humans Immunity, Innate Interferon-Induced Helicase, IFIH1 Lysosomes/drug effects,genetics,metabolism Melanoma/immunology,pathology,therapy Mice Microtubule-Associated Proteins/metabolism,physiology Phagosomes/drug effects,genetics,metabolism Poly C/pharmacology Polyethyleneimine/pharmacology Proto-Oncogene Proteins c-bcl-2/metabolism RNA, Double-Stranded
Chemicals
Antineoplastic Agents Atg5 protein, mouse Autophagy-Related Protein 5 Map1lc3b protein, mouse Microtubule-Associated Proteins Pmaip1 protein, mouse Proto-Oncogene Proteins c-bcl-2 RNA, Double-Stranded Poly C Polyethyleneimine Ifih1 protein, mouse DEAD-box RNA Helicases Interferon-Induced Helicase, IFIH1
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Tormo Damià
Melanoma Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Checińska Agnieszka
Alonso-Curbelo Direna
Pérez-Guijarro Eva
Cañón Estela
Riveiro-Falkenbach Erica
Calvo Tonantzin G
Larribere Lionel
Megías Diego
Mulero Francisca
Piris Miguel A
Dash Rupesh
Barral Paola M
Rodríguez-Peralto José L
Ortiz-Romero Pablo
Tüting Thomas
Fisher Paul B
Soengas María S
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2009.07.004
Published
2009-08-04
Pages
103-14
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2851205
Subset
IM
Grants
NCI NIH HHS · R01 CA107237 · United States
NCI NIH HHS · R01 CA107237-05 · United States
NIGMS NIH HHS · R01 GM068448 · United States
Corrections
CommentIn
PMID: 19647216
External Links
PubMed source DOI: 10.1016/j.ccr.2009.07.004 PMC Full Text View journal details
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