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A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death

Abhishek D Garg, Dmitri Krysko UGent, Tom Verfaillie, Agnieszka Kaczmarek UGent, Gabriela B Ferreira, Thiery Marysael, Noemi Rubio, Malgrozata Firczuk, Chantal Mathieu and Anton JM Roebroek, et al. (2012) EMBO JOURNAL. 31(5). p.1062-1079
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
DAMPs, cancer, calreticulin, immunogenic apoptosis, photodynamic therapy, MEDIATED PHOTODYNAMIC THERAPY, ENDOPLASMIC-RETICULUM STRESS, UNFOLDED PROTEIN RESPONSE, FIND-ME SIGNAL, NITRIC-OXIDE, PHOSPHATIDYLINOSITOL 3-KINASE, MEMBRANE-PERMEABILITY, MOLECULAR EFFECTORS, ANTICANCER THERAPY, ANTITUMOR IMMUNITY
journal title
EMBO JOURNAL
Embo J.
volume
31
issue
5
pages
1062 - 1079
Web of Science type
Article
Web of Science id
000301342500004
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
9.822 (2012)
JCR rank
17/288 (2012)
JCR quartile
1 (2012)
ISSN
0261-4189
DOI
10.1038/emboj.2011.497
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2085139
handle
http://hdl.handle.net/1854/LU-2085139
date created
2012-04-12 15:00:18
date last changed
2014-05-12 10:59:31
@article{2085139,
  abstract     = {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.},
  author       = {Garg, Abhishek D and Krysko, Dmitri and Verfaillie, Tom and Kaczmarek, Agnieszka and Ferreira, Gabriela B and Marysael, Thiery and Rubio, Noemi and Firczuk, Malgrozata and Mathieu, Chantal and Roebroek, Anton JM and Annaert, Wim and Golab, Jakub and de Witte, Peter and Vandenabeele, Peter and Agostinis, Patrizia},
  issn         = {0261-4189},
  journal      = {EMBO JOURNAL},
  keyword      = {DAMPs,cancer,calreticulin,immunogenic apoptosis,photodynamic therapy,MEDIATED PHOTODYNAMIC THERAPY,ENDOPLASMIC-RETICULUM STRESS,UNFOLDED PROTEIN RESPONSE,FIND-ME SIGNAL,NITRIC-OXIDE,PHOSPHATIDYLINOSITOL 3-KINASE,MEMBRANE-PERMEABILITY,MOLECULAR EFFECTORS,ANTICANCER THERAPY,ANTITUMOR IMMUNITY},
  language     = {eng},
  number       = {5},
  pages        = {1062--1079},
  title        = {A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death},
  url          = {http://dx.doi.org/10.1038/emboj.2011.497},
  volume       = {31},
  year         = {2012},
}

Chicago
Garg, Abhishek D, Dmitri Krysko, Tom Verfaillie, Agnieszka Kaczmarek, Gabriela B Ferreira, Thiery Marysael, Noemi Rubio, et al. 2012. “A Novel Pathway Combining Calreticulin Exposure and ATP Secretion in Immunogenic Cancer Cell Death.” Embo Journal 31 (5): 1062–1079.
APA
Garg, Abhishek D, Krysko, D., Verfaillie, T., Kaczmarek, A., Ferreira, G. B., Marysael, T., Rubio, N., et al. (2012). A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO JOURNAL, 31(5), 1062–1079.
Vancouver
1.
Garg AD, Krysko D, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO JOURNAL. 2012;31(5):1062–79.
MLA
Garg, Abhishek D, Dmitri Krysko, Tom Verfaillie, et al. “A Novel Pathway Combining Calreticulin Exposure and ATP Secretion in Immunogenic Cancer Cell Death.” EMBO JOURNAL 31.5 (2012): 1062–1079. Print.