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Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor α-induced necroptosis

Bram Laukens UGent, Claudia Jennewein, Barbara Schenk, Nele Vanlangenakker UGent, Alexander Schier, Silvia Cristofanon, Kerry Zobel, Kurt Deshayes, Domagoj Vucic and Irmela Jeremias, et al. (2011) NEOPLASIA. 13(10). p.971-U125
abstract
Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD-or caspase-8-deficient leukemia cells for TNF alpha-induced necroptosis in a synergistic manner. In contrast to TNF alpha, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smacmimetic- and TNF alpha-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNF alpha trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD. fmk fails to block Smac mimetic-and TNF alpha-triggered cell death in FADD-or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic-and TNFa-induced cell death in FADD-or caspase-8-deficient. Thus, Smac mimetic enhances TNFa-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNF alpha-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNF alpha-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.
Please use this url to cite or link to this publication:
author
organization
alternative title
Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor alpha-induced necroptosis
year
type
journalArticle (original)
publication status
published
subject
keyword
DEATH, IN-VITRO, RIP1 KINASE, DEPENDENT APOPTOSIS, KAPPA-B ACTIVATION, CANCER, FAS, MOLECULE, RECEPTOR, CIAP1
journal title
NEOPLASIA
Neoplasia
volume
13
issue
10
pages
971 - U125
Web of Science type
Article
Web of Science id
000297640400008
JCR category
ONCOLOGY
JCR impact factor
5.946 (2011)
JCR rank
21/190 (2011)
JCR quartile
1 (2011)
ISSN
1522-8002
DOI
10.1593/neo.11610
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1996538
handle
http://hdl.handle.net/1854/LU-1996538
date created
2012-01-19 13:17:59
date last changed
2012-06-26 14:32:30
@article{1996538,
  abstract     = {Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD-or caspase-8-deficient leukemia cells for TNF alpha-induced necroptosis in a synergistic manner. In contrast to TNF alpha, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smacmimetic- and TNF alpha-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNF alpha trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD. fmk fails to block Smac mimetic-and TNF alpha-triggered cell death in FADD-or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic-and TNFa-induced cell death in FADD-or caspase-8-deficient. Thus, Smac mimetic enhances TNFa-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNF alpha-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNF alpha-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.},
  author       = {Laukens, Bram and Jennewein, Claudia and Schenk, Barbara and Vanlangenakker, Nele and Schier, Alexander and Cristofanon, Silvia and Zobel, Kerry and Deshayes, Kurt and Vucic, Domagoj and Jeremias, Irmela and Bertrand, Mathieu and Vandenabeele, Peter and Fulda, Simone},
  issn         = {1522-8002},
  journal      = {NEOPLASIA},
  keyword      = {DEATH,IN-VITRO,RIP1 KINASE,DEPENDENT APOPTOSIS,KAPPA-B ACTIVATION,CANCER,FAS,MOLECULE,RECEPTOR,CIAP1},
  language     = {eng},
  number       = {10},
  pages        = {971--U125},
  title        = {Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor \ensuremath{\alpha}-induced necroptosis},
  url          = {http://dx.doi.org/10.1593/neo.11610},
  volume       = {13},
  year         = {2011},
}

Chicago
Laukens, Bram, Claudia Jennewein, Barbara Schenk, Nele Vanlangenakker, Alexander Schier, Silvia Cristofanon, Kerry Zobel, et al. 2011. “Smac Mimetic Bypasses Apoptosis Resistance in FADD- or Caspase-8-deficient Cells by Priming for Tumor Necrosis Factor Α-induced Necroptosis.” Neoplasia 13 (10): 971–U125.
APA
Laukens, B., Jennewein, C., Schenk, B., Vanlangenakker, N., Schier, A., Cristofanon, S., Zobel, K., et al. (2011). Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor α-induced necroptosis. NEOPLASIA, 13(10), 971–U125.
Vancouver
1.
Laukens B, Jennewein C, Schenk B, Vanlangenakker N, Schier A, Cristofanon S, et al. Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor α-induced necroptosis. NEOPLASIA. 2011;13(10):971–U125.
MLA
Laukens, Bram, Claudia Jennewein, Barbara Schenk, et al. “Smac Mimetic Bypasses Apoptosis Resistance in FADD- or Caspase-8-deficient Cells by Priming for Tumor Necrosis Factor Α-induced Necroptosis.” NEOPLASIA 13.10 (2011): 971–U125. Print.