Journal
EMBO JOURNAL
Volume 31, Issue 5, Pages 1062-1079Publisher
WILEY
DOI: 10.1038/emboj.2011.497
Keywords
calreticulin; cancer; DAMPs; immunogenic apoptosis; photodynamic therapy
Categories
Funding
- Fund for Scientific Research Flanders (FWO-Vlaanderen) [G.0728.10]
- KU Leuven [GOA/11/009, GOA/12/016]
- FWO-Vlaanderen [G.0661.09, G.0875.11, G.0973.11, G.0529.08, G.0689.10]
- Interuniversity Attraction Poles Programme
- F.R.S-FNRS [F/5/4/5-MCF/KP]
- VIB
- Ghent University
- Federal Research Program [IAP 6/18]
- European Research Program FP6 ApopTrain [MRTN-CT-035624]
- FP7 Apo-Sys [200767]
- Euregional PACTII
- Flemish Government [BOF09/01M00709]
- Ministry of Science and Higher education [N N401 037138]
- European Regional Development Fund through Innovative Economy [POIG.01.01.02-00-008/08]
- Foundation for Polish Science
- EU
- FWO
- Hercules Foundation [AUGE/09/040, AKUL/09/037]
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Surface-exposed calreticulin (ecto-CRT) and secreted ATP are crucial damage-associated molecular patterns (DAMPs) for immunogenic apoptosis. Inducers of immunogenic apoptosis rely on an endoplasmic reticulum (ER)based (reactive oxygen species (ROS)-regulated) pathway for ecto-CRT induction, but the ATP secretion pathway is unknown. We found that after photodynamic therapy (PDT), which generates ROS-mediated ER stress, dying cancer cells undergo immunogenic apoptosis characterized by phenotypic maturation (CD80(high), CD83(high), CD86(high), MHC-IIhigh) and functional stimulation (NOhigh, IL-10(absent), IL-1 beta(high)) of dendritic cells as well as induction of a protective antitumour immune response. Intriguingly, early after PDT the cancer cells displayed ecto-CRT and secreted ATP before exhibiting biochemical signatures of apoptosis, through overlapping PERK-orchestrated pathways that require a functional secretory pathway and phosphoinositide 3-kinase (PI3K)-mediated plasma membrane/extracellular trafficking. Interestingly, eIF2 alpha phosphorylation and caspase-8 signalling are dispensable for this ecto-CRT exposure. We also identified LRP1/CD91 as the surface docking site for ecto-CRT and found that depletion of PERK, PI3K p110 alpha and LRP1 but not caspase-8 reduced the immunogenicity of the cancer cells. These results unravel a novel PERK-dependent subroutine for the early and simultaneous emission of two critical DAMPs following ROS-mediated ER stress. The EMBO Journal (2012) 31, 1062-1079. doi: 10.1038/emboj.2011.497; Published online 17 January 2012 Subject Categories: signal transduction; molecular biology of disease
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