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

Cancer Cell. 2009 Aug 4;16(2):103-14. doi: 10.1016/j.ccr.2009.07.004.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Autophagy / drug effects
  • Autophagy / genetics
  • Autophagy / immunology*
  • Autophagy-Related Protein 5
  • Cell Line, Tumor
  • Cells, Cultured
  • DEAD-box RNA Helicases / metabolism
  • Endosomes / drug effects
  • Endosomes / genetics
  • Endosomes / metabolism
  • Humans
  • Immunity, Innate*
  • Interferon-Induced Helicase, IFIH1
  • Lysosomes / drug effects
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / therapy
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology
  • Phagosomes / drug effects
  • Phagosomes / genetics
  • Phagosomes / metabolism
  • Poly C / pharmacology
  • Polyethyleneimine / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Double-Stranded

Substances

  • Antineoplastic Agents
  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • MAP1LC3 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