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RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis

S Loeder, M Schirmer, H Schoeneberger, S Cristofanon, J Leibacher, Nele Vanlangenakker UGent, Mathieu Bertrand UGent, Peter Vandenabeele UGent, I Jeremias and K-M Debatin, et al. (2012) LEUKEMIA. 26(5). p.1020-1029
abstract
Evasion of apoptosis may contribute to poor treatment response in pediatric acute lymphoblastic leukemia (ALL), calling for novel treatment strategies. Here, we report that inhibitors of apoptosis (IAPs) at subtoxic concentrations cooperate with various anticancer drugs (that is, AraC, Gemcitabine, Cyclophosphamide, Doxorubicin, Etoposide, Vincristine and Taxol) to induce apoptosis in ALL cells in a synergistic manner as calculated by combination index and to reduce long-term clonogenic survival. Importantly, we identify RIP1 as a critical regulator of this synergism of IAP inhibitors and AraC that mediates the formation of a RIP1/FADD/caspase-8 complex via an autocrine/paracrine loop of tumor necrosis factor-alpha (TNF alpha). Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3, mitochondrial perturbations and apoptosis. Similarly, inhibition of RIP1 kinase activity by Necrostatin-1 or blockage of TNF alpha by Enbrel inhibits IAP inhibitor-and AraC-triggered interaction of RIP1, FADD and caspase-8 and apoptosis. In contrast to malignant cells, IAP inhibitors and AraC at equimolar concentrations are non-toxic to normal peripheral blood lymphocytes or mesenchymal stromal cells. Thus, our findings provide first evidence that IAP inhibitors present a promising strategy to prime childhood ALL cells for chemotherapy-induced apoptosis in a RIP1-dependent manner. These data have important implications for developing apoptosis-targeted therapies in childhood leukemia.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ALL, RIP1, ACUTE LYMPHOBLASTIC-LEUKEMIA, ALPHA-DEPENDENT APOPTOSIS, apoptosis, IAPs, ACTIVATION, CANCER, XIAP, NF-KAPPA-B, TRAIL-INDUCED APOPTOSIS, PANCREATIC-CARCINOMA, DEATH, ANTAGONISTS
journal title
LEUKEMIA
Leukemia
volume
26
issue
5
pages
1020 - 1029
Web of Science type
Article
Web of Science id
000303883500021
JCR category
HEMATOLOGY
JCR impact factor
10.164 (2012)
JCR rank
2/66 (2012)
JCR quartile
1 (2012)
ISSN
0887-6924
DOI
10.1038/leu.2011.353
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
additional info
correction of author names published in Leukemia (2012) 26, 1745; doi: 10.1038/leu.2012.131
copyright statement
I have transferred the copyright for this publication to the publisher
id
2153315
handle
http://hdl.handle.net/1854/LU-2153315
date created
2012-06-14 11:55:28
date last changed
2014-05-12 11:00:31
@article{2153315,
  abstract     = {Evasion of apoptosis may contribute to poor treatment response in pediatric acute lymphoblastic leukemia (ALL), calling for novel treatment strategies. Here, we report that inhibitors of apoptosis (IAPs) at subtoxic concentrations cooperate with various anticancer drugs (that is, AraC, Gemcitabine, Cyclophosphamide, Doxorubicin, Etoposide, Vincristine and Taxol) to induce apoptosis in ALL cells in a synergistic manner as calculated by combination index and to reduce long-term clonogenic survival. Importantly, we identify RIP1 as a critical regulator of this synergism of IAP inhibitors and AraC that mediates the formation of a RIP1/FADD/caspase-8 complex via an autocrine/paracrine loop of tumor necrosis factor-alpha (TNF alpha). Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3, mitochondrial perturbations and apoptosis. Similarly, inhibition of RIP1 kinase activity by Necrostatin-1 or blockage of TNF alpha by Enbrel inhibits IAP inhibitor-and AraC-triggered interaction of RIP1, FADD and caspase-8 and apoptosis. In contrast to malignant cells, IAP inhibitors and AraC at equimolar concentrations are non-toxic to normal peripheral blood lymphocytes or mesenchymal stromal cells. Thus, our findings provide first evidence that IAP inhibitors present a promising strategy to prime childhood ALL cells for chemotherapy-induced apoptosis in a RIP1-dependent manner. These data have important implications for developing apoptosis-targeted therapies in childhood leukemia.},
  author       = {Loeder, S and Schirmer, M and Schoeneberger, H and Cristofanon, S and Leibacher, J and Vanlangenakker, Nele and Bertrand, Mathieu and Vandenabeele, Peter and Jeremias, I and Debatin, K-M and Fulda, S},
  issn         = {0887-6924},
  journal      = {LEUKEMIA},
  keyword      = {ALL,RIP1,ACUTE LYMPHOBLASTIC-LEUKEMIA,ALPHA-DEPENDENT APOPTOSIS,apoptosis,IAPs,ACTIVATION,CANCER,XIAP,NF-KAPPA-B,TRAIL-INDUCED APOPTOSIS,PANCREATIC-CARCINOMA,DEATH,ANTAGONISTS},
  language     = {eng},
  number       = {5},
  pages        = {1020--1029},
  title        = {RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis},
  url          = {http://dx.doi.org/10.1038/leu.2011.353},
  volume       = {26},
  year         = {2012},
}

Chicago
Loeder, S, M Schirmer, H Schoeneberger, S Cristofanon, J Leibacher, Nele Vanlangenakker, Mathieu Bertrand, et al. 2012. “RIP1 Is Required for IAP Inhibitor-mediated Sensitization of Childhood Acute Leukemia Cells to Chemotherapy-induced Apoptosis.” Leukemia 26 (5): 1020–1029.
APA
Loeder, S., Schirmer, M., Schoeneberger, H., Cristofanon, S., Leibacher, J., Vanlangenakker, N., Bertrand, M., et al. (2012). RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis. LEUKEMIA, 26(5), 1020–1029.
Vancouver
1.
Loeder S, Schirmer M, Schoeneberger H, Cristofanon S, Leibacher J, Vanlangenakker N, et al. RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis. LEUKEMIA. 2012;26(5):1020–9.
MLA
Loeder, S, M Schirmer, H Schoeneberger, et al. “RIP1 Is Required for IAP Inhibitor-mediated Sensitization of Childhood Acute Leukemia Cells to Chemotherapy-induced Apoptosis.” LEUKEMIA 26.5 (2012): 1020–1029. Print.